Interactions of early actinides with biologically-relevant organic molecules including carboxylates, amino acids and proteins

Abstract

This Perspective article reviews the current knowledge regarding the interaction of actinide elements with biomolecules, particularly amino acids, peptides, and proteins. We assess the significance of these interactions, especially in connection to nuclear waste disposal and the potential role of these interactions in the origin of life. Actinides have been observed to form stable complexes with carboxylate groups, resulting in oligomerization and affecting their environmental mobility. The text discusses the complex coordination chemistry of actinides, including the prevalence of hexanuclear An⁴⁺ clusters, and the implications of these findings for actinide transport and bioavailability as well as remaining challenges especially for mechanistic and thermodynamic aspects of this chemistry. Recent discoveries of lanthanide- and actinide-dependent enzymes, including methanol dehydrogenase and lanmodulin, suggest a potential for these elements to have been actively involved in early metabolic processes, rather than solely acting as environmental stressors. Despite the absence of direct evidence connecting natural reactors to the process of abiogenesis, a comprehensive understanding of actinide–biomolecule interactions is imperative for the evaluation of the nuclear geyser model and the resolution of the long-term challenges posed by the management of radioactive waste.

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Satoru Tsushima

Prof. Satoru Tsushima completed his Ph.D. at the University of Tokyo in 1999. He assumed a faculty position at the Nagoya University in 2003, and later relocated to Stockholm University. In 2006, he was awarded a stipend from the Alexander von Humboldt foundation and moved to Grenoble, France, to work at the ESRF, and later became a senior scientist at Helmholtz-Zentrum Dresden-Rossendorf. Since 2017, he has also been a specially-appointed associate professor at the Institute of Science Tokyo. His current research interest pertains to the implementation of computational chemistry in the domain of actinide science (Photo copyright HZDR/C.Reichelt).

Koichiro Takao

Prof. Koichiro Takao (previously “Koichiro Mizuoka”) finished his Ph.D in 2006 at Tokyo Institute of Technology (“Institute of Science Tokyo” today). He further explored actinide chemistry to develop a simple and versatile reprocessing principle at TokyoTech (2006–2008) and to deepen fundamental coordination chemistry of Th, U, and Np at HZDR (2008–2010). After accumulating his professional career as an assistant professor (2010–2015), he was appointed to an associate professor in the Laboratory for Zero-Carbon Energy, Institute of Science Tokyo in 2015. His research interest is still fundamental coordination chemistry of actinides, while it is closely related to nuclear fuel recycling, U harvesting from seawater, chemical utilization of depleted U, and flexible management of nuclear wastes.

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1. Background

Despite the persistent controversy surrounding abiogenesis, increasing evidence suggests life may have emerged in a radioactive environment, supporting the nuclear geyser model.^1,2 None of the previously-proposed hypotheses on the origin of life can provide the energy flux of ionizing radiation required to synthesize organic materials as demonstrated by the Miller–Urey-experiment.³ By contrast, a natural nuclear reactor could have afforded high-energy flux which could have initiated chemical reactions to produce major biological molecules, including amino acids, nucleotides, and sugars from “raw” molecules (H₂O, N₂, and CO₂).⁴ The nuclear geyser model asserts that natural nuclear fission reactor(s) on the Hadean Earth served as the driving force behind the emergence of life.

During this period, the isotopic proportion of fissile ²³⁵U was as high as 20%, significantly higher than the current 0.72%. Under such circumstances, even low-grade uranium ore could have served as a functional nuclear reactor, given the presence of water as a neutron moderator. It should also be considered that the Moon was closer to the Earth in the Hadean Era, resulting in enormous tidal variations.

Natural nuclear reactors could have facilitated the circulation of material and energy, enabling chemical reactions leading to the synthesis of complex organic compounds including amino acids, peptides, and nucleobases. This process may have generated the earliest forms of metabolism, with uranium acting not just as fissile material but also as oligomeric catalyst and coordinating ion for prebiotic metalloenzymes.⁵ Furthermore, increasing evidence for proteins and bacteria dependent on lanthanides or actinides^6–11 supports the notion that these elements played an essential role in early metabolism. Paleontological studies have unearthed the earliest eukaryotic fossil from the Paleoproterozoic Francevillian Group in Gabon, a region where natural nuclear reactor once existed.¹²

Taking into account these observations, and given the rich redox chemistry exhibited by actinides,¹³ along with their remarkable coordinating ability,¹⁴ their interaction with amino acids and subsequent oligomerization likely played a key role in prebiotic evolution and homochirality. Previous studies on the interaction between actinide and amino acid or with primitive peptide such as glutathione have not discussed the potential importance of these interactions in prebiotic systems.

Despite that the nuclear geyser model still remains hypothetical, and linking actinide with the origin of life being controversial, it is also important to assess whether current biochemical knowledge of actinide-amino acid interaction aligns with the nuclear geyser model to test its validity. Fig. 1 depicts the circulation of materials on Hadean to Eoarchean Earth with the focus on uranium (+ minor actinides) and amino acids. This model proposes that natural nuclear reactors contributed to amino acid formation, which then facilitated the emergence of actinide carboxylates and related oligomers, transported in the geosphere. This process may have led to the formation of primitive proteins and enzymes potentially utilizing actinide ions.

Fig. 1 Potential circulation routes of materials on Hadean to Eoarchean Earth as well as the roles of uranium, minor actinides, amino acids and their derivatives. This concept is based on a nuclear geyser model (see text and references therein), though the idea remains hypothetical. Scaling is enlarged arbitrarily for a selected group of objects.

This Perspective aims to provide a systematic review of past studies on the interactions of actinides with amino acids and proteins, to consider the broader implications of this rapidly developing field of research. Ultimately, we would like to help verify the nuclear geyser model from a chemical as well as biophysical perspectives rather than from an astronomical standpoint, and to suggest a research direction for that purpose.

2. Actinide coordination with carboxylates and amino acids

2.1. UO₂²⁺ interaction with amino acids

We initiate our discussions with the UO₂²⁺ ion, which is one of the most prevalent actinide ions. The complexation behaviour of UO₂²⁺ with general carboxylates (RCOO⁻) has been thoroughly examined and documented,¹⁵ and we do not go in depth to this direction in this Perspective. The interaction of UO₂²⁺ with amino acids (AAs) in aqueous solution has been the subject of extensive research.^16–19 Generally, ligand coordination to UO₂²⁺ is constrained to its equatorial plane, with a preferred coordination number of 5. The predominant interactions of UO₂²⁺ with AAs or proteins involve carboxylic groups, including those from the sidechains of Asp and Glu. Interactions with Tyr and His sidechains have also been reported.^18,20,21 Gas-phase experiments corroborate UO₂²⁺ coordination to the carboxylic group of Asp, the thiolate group of Cys, and the imidazole group of His.²² It is also important to note that there are a number of examples of hydrogen bonding to the “yl”-oxygen of UO₂²⁺,²³ despite the “yl”-oxygen being generally inert. Such interaction frequently occurs in instances when UO₂²⁺ is situated within a hydrophobic environment, such as within a folded protein,^24,25 or when hydrogen atoms from free AAs are in close proximity to UO₂²⁺. In the case of the ternary complex of uranyl(VI)–Gly–fluoride, NMR spectroscopy has confirmed the presence of chelate-bonded Gly.²⁶

Surprisingly, the number of reported crystal structures of UO₂²⁺ complexes with AAs is rather limited. A search of the Cambridge Structural Database revealed only two documented instances of crystal structures of UO₂²⁺ complexes with AA, both of which are Gly and its deprotonated form (Gly⁻) through O^O bidentate coordination.^27,28 Other examples include its N,N,N-trimethylated derivative (i.e., betaine),²⁹ and iminodiacetate.³⁰ An N^O bidentate coordination, which would be expected to form a stable 5-membered chelate ring according to conventional coordination chemistry, has not been observed in a crystal structure of UO₂²⁺. However, this binding mode is plausible, as evidenced by the NMR spectrum of an aqueous UO₂²⁺–Gly–F⁻ system,²⁶ and has been demonstrated with related ligands such as iminodiacetate,^31,32 nitrilotriacetate,³³ EDTA⁴⁻,³³ and His-based Schiff bases.³⁴ Another O^O coordination mode of Gly and Ala is utilized to form infinite 1D coordination polymers of UO₂²⁺ (Fig. 2(A) and (B)), where syn–syn bridging of these AAs occurs between neighbouring UO₂²⁺ units,^23,35,36 thereby inhibiting further growth of the UO₂²⁺–μ₃-O(H) 2D sheets of meta-schoepite, (UO₂)₂O(OH)₆·5H₂O, (Fig. 2(C))³⁷ that initially form upon UO₂²⁺ hydrolysis.

Fig. 2 Infinite 1D coordination polymers of UO₂²⁺ composed of uranyl pentagonal bipyramids that are chelated by Gly (A) and Ala (B) in a syn–syn bridging (top and side views) reported by Forbes and coauthors³⁵ and infinite 2D sheet of meta-schoepite, (UO₂)₂O(OH)₆·5H₂O (C), along a- and b-axes reported by Weller et al.³⁷

2.2. An⁴⁺ carboxylates and hexamers (An = Th, U, Np, Pu) 

While the formation of mononuclear complexes of actinide with simple AAs has little practical relevance and remains largely a subject of laboratory research, the oligomerization of actinides with AAs and other carboxylates is more pertinent to the nuclear industry and to the environmental concerns. While the hydrolysed UO₂²⁺ coordination polymers with Gly and Ala have been exemplified above, oligomerization and polymerization of actinides is more frequently observed in the tetravalent oxidation states (An⁴⁺, An = Th, U, Np, Pu). This phenomenon can be attributed to the pronounced hydrolytic tendency of An⁴⁺, which is characterized by the presence of high charge densities. These charge densities are conductive to promote polynucleation through olation and oxolation.³⁸ The final product resulting from the hydrolysis of An⁴⁺ is AnO₂(c), which exhibits fluorite-like crystal structure. This topic will be discussed in detail in the subsequent section.

In the presence of carboxylate (RCOO⁻), it is necessary to consider the competition between the hydrolytic polynucleation of An⁴⁺ and coordination interactions of RCOO⁻ with An⁴⁺, that may occur in a concurrent manner. Although a variety of coordination manners of RCOO⁻ are theoretically possible, the syn–syn bridging by μ-RCOO⁻ is exclusively observed in the cases of An⁴⁺. In the early era of actinide coordination chemistry, isolated compounds from An⁴⁺–carboxylate systems were erroneously assigned to simple compound such as [An(RCOO)₄]_n, where the metal ions were supposed to be interconnected by μ-RCOO⁻, to form infinite 1D coordination polymers.¹⁵ Even in the aftermath of the hydrolysis of An⁴⁺, the polymeric structure were considered to remain largely intact, with partial replacement of RCOO⁻ by OH⁻. Today, it is hard to accept such an infinite 1D coordination polymer to occur as a soluble species in mother liquors. In fact, already in 1920s, the presence of Th(IV) oligomeric species has been suggested through the study on the Th⁴⁺–HCOO⁻ system to propose the compound [Th₃(OH)₅(HCOO)₆]·A·nH₂O (A = ClO₄, NO₃, HCOO, SCN, ClO₃) first by Weinland and Stark in 1926 ³⁹ and later by Reihlen and Debus in 1929.⁴⁰

Eight decades later, we have successfully identified the precise molecular and crystal structures of polynuclear complexes of Th⁴⁺ and U⁴⁺ with HCOO⁻ by means of single crystal X-ray diffraction.⁴¹ These An⁴⁺ compounds exhibit common molecular structures consisting of discrete hexanuclear complexes, [An₆(μ₃-O)₄(μ₃-OH)₄(μ-HCOO)₁₂(H₂O)₆] (An = Th, U; Fig. 3(A)), where μ₃-O²⁻/OH⁻ are included as tripodal connectors for three An⁴⁺ ions to form an An⁴⁺ hexamer (Fig. 3(B)). The octahedral core of the {An⁴⁺}₆ structure is further decorated by μ-HCOO⁻, which serves to bind each pair of neighbouring An⁴⁺ ions. Note that the compositions of the compounds we identified are nearly double as those suggested in 1920s. This results in the following formula: [Th₆(OH)₁₀(HCOO)₁₂]·A·nH₂O = [Th₆(μ₃-O)₄(μ₃-OH)₄(HCOO)₁₂]·2HA·2(n+1)H₂O, where some variations in co-crystallized salts/acids can be found. Furthermore, extended X-ray absorption spectroscopy (EXAFS) and UV-vis spectroscopy successfully confirmed the formation of these [An₆(μ₃-O)₄(μ₃-OH)₄(μ-HCOO)₁₂(H₂O)₆] complexes in aqueous solutions (Fig. 3(C) and (D)), thereby establishing a clear connection between solution chemistry and solid-state structures. Although the formation of such an An₆O₈ core unit has been previously observed in diphenylphosphate and triflate systems,^42,43 in which the deprotonated phosphate diesters or triflate anions are located at the edges of the {An⁴⁺}₆ octahedron in a manner analogous to μ-HCOO⁻ of Fig. 3(A), research activities on polynuclear complexes of hydrolysed An⁴⁺ with μ-RCOO⁻ and related organic molecules have been revitalized.

Fig. 3 Structural chemistry of An⁴⁺–RCOO⁻ hexanuclear complexes reported so far. Whole molecular structure of [Th₆(μ₃-O)₄(μ₃-OH)₄(μ-HCOO)₁₂(H₂O)₆] (A, where H atoms were omitted for clarity) and its An₆O₈ core (B) together with Fourier transforms of k³-weighted L_III-edge EXAFS spectra of An⁴⁺ (An = Th (C, 50 mM),⁴¹ U (D, 15 mM),⁴¹ Np (E, 25 mM),⁴⁶ Pu (F, 3.9 mM)⁵¹) in aqueous solutions containing 1 M RCOOH (R = H, CH₃) under specific pH conditions. Panel (C), (D), (E), and (F) were reproduced from ref. 41, 46 and 51, respectively, with permission from Wiley-VCH GmbH (Copyright 2009) and American Chemical Society (Copyright 2012, 2022).

As a matter of fact, this class of chemistry was further expanded to the heavier tetravalent actinides, Np⁴⁺ and Pu⁴⁺. In connection with our findings of the hydrolysed hexamers of Th⁴⁺ and U⁴⁺ decorated by μ-HCOO⁻ described above,⁴¹ and the following works with PhCOO⁻ (ref. 44) and CH₃COO⁻/ClCH₂COO⁻,⁴⁵ we have explored solution coordination chemistry of Np⁴⁺ under the presence of RCOO⁻ (R = H, CH₃) in aqueous systems by means of UV-vis and EXAFS.⁴⁶ Predominant formation of [Np₆(μ₃-O)₄(μ₃-OH)₄(μ-RCOO)₁₂] was commonly observed in both R = H, CH₃ systems of 1.00 M RCOOH at pH ≳ 2 as pronounced by representative intermetallic interactions in Fourier transforms of the EXAFS spectra (Fig. 3(E)) at R + Δ = 3.80–3.81 Å and 5.39–5.40 Å for adjacent and diagonal pairs of Np atoms, respectively. The presence of the terminal H₂O observed in the X-ray structures with the lighter An⁴⁺ (Fig. 3(A)) could not be unambiguously confirmed in the case of Np⁴⁺ complexes due to uncertainty in the EXAFS analysis. The coordinating water molecules may not be present, considering the smaller ionic radius of Np⁴⁺ (0.98 Å, CN = 8) compared with Th⁴⁺ (1.05 Å for CN = 8, 1.09 Å for CN = 9) and U⁴⁺ (1.00 Å for CN = 8, 1.05 Å for CN = 9).⁴⁷ However, this issue remains controversial, as both the presence and the absence of an H₂O molecule in hexanuclear complexes of the smaller Pu⁴⁺ have been reported in the literatures (vide infra).^48,49 The EXAFS analysis of aqueous solutions revealed a distinction between the distances of Np–μ₃-O²⁻ (2.22–2.23 Å) and Np–μ₃-OH⁻ (2.42–2.43 Å). This observation is noteworthy, as such distinctions are often ambiguous in crystal structures due to the inherent disorder of μ₃-O²⁻/OH⁻ as exemplified by [Th₆(μ₃-O)₄(μ₃-OH)₄(RCOO)₁₂(H₂O)₆] (R = H, CH₃, CH₂Cl)⁴⁵ deposited under the absence of NaClO₄ in the mother liquors. An analogous Np⁴⁺ hexamer decorated by PhCOO⁻ was also observed in an EtOH/aqueous 1 : 1 mixture, while this solid phase was characterized only by powder XRD.⁵⁰ Subsequent to the X-ray crystallographic studies on Pu⁴⁺ hexamers with Gly and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (H_nDOTAⁿ⁻⁴), which we will discuss later,^48,49 the CEA group undertook an examination of solution coordination chemistry in an aqueous Pu⁴⁺–CH₃COO⁻ system.⁵¹ In a manner analogous to the Np⁴⁺ case,⁴⁶ the Pu₆O₈ cluster decorated by the syn–syn bridging CH₃COO⁻ such as [Pu₆(μ₃-O)₄(μ₃-OH)₄(μ-CH₃COO)₁₂(H₂O)₆] was found to be formed predominantly under the presence of 1 M CH₃COOH at pH 4.5 (Fig. 3(F)), where H₂O molecule capping each vertex of the {Pu⁴⁺}₆ octahedral core was also included in the EXAFS fit with a fixed coordination number for each shell. In a manner analogous to Np⁴⁺, PhCOO⁻ also allowed to yield a Pu⁴⁺ hexanuclear cluster, [Pu₆(μ₃-O)₄(μ₃-OH)₄(PhCOO)₁₂(H₂O)₄], wherein only eight PhCOO⁻ are involved in the syn–syn bridging between neighbouring Pu⁴⁺ atoms, and the remaining four PhCOO⁻ are either monodentate or bidentate-chelating to bind to a single Pu⁴⁺.⁵⁰

While the majority of reported works remain focused on Th⁴⁺ and U⁴⁺, in contrast to the limited numbers of known examples of Np⁴⁺ and Pu⁴⁺, several review articles are currently available that offer comprehensive summaries on the coordination chemistry of polynuclear An⁴⁺ complexes with RCOO⁻ and polycarboxylates.^38,52–56 These two ligand systems, RCOO⁻ and polycarboxylates, are closely related to each other, making it difficult to distinguish them distinctly. However, the former (RCOO⁻) places greater emphasis on the fundamental aspects of this structural chemistry class, and it is also relevant to understanding the reaction mechanisms of AnO₂ colloid formation, especially for PuO₂ colloidal nanoparticles. The main concern of the latter (polycarboxylates) is the utilization of An₆O₈ core unit as building blocks of metal–organic frameworks (MOFs) mimicking non-radioactive tetravalent transition metal ions, most typically Zr⁴⁺, to afford UiO-6X (X = 6, 7) type MOF structures.

In contrast to RCOO⁻, the coordination chemistry of An⁴⁺ with AAs is even more limited despite their higher biological relevance compared to RCOO⁻. In the majority of instances, this coordination chemistry is exclusively confined to the systems with Gly. The [An₆(μ₃-O)₄(μ₃-OH)₄(μ-Gly⁻)_x(μ-Gly)_12−x(H₂O)₆]^12−x was obtained commonly for An = Th (x = 6)^57,58 and U (x = 0).⁵⁹ In these cases, the syn–syn bridging manner of the carboxylate moiety of Gly and/or its deprotonated form (Gly⁻) followed that observed for RCOO⁻ (Fig. 4(A)). Using EXAFS, we observed predominant formation of [Np₆(μ₃-O)₄(μ₃-OH)₄(μ-AA)₁₂]^y+ (AA = Gly, Ala, Cys; 0 ≤ y ≤ 12) in aqueous solutions under acidic conditions even below pH 1 (Fig. 4(B)).⁴⁶ It is important to note that no significant effects of sidechains (R) of Ala (R = –CH₃) and Cys (R = –CH₂SH) have appeared in the actual Np⁴⁺ hexamer formation. The initial report on the Pu⁴⁺ version of the hexanuclear coordination clusters in this context is X-ray structure determination of [Pu₆(μ₃-O)₄(μ₃-OH)₄(μ-Gly)₁₂(H₂O)₆]¹²⁺ co-crystallized with Li⁺, Cl⁻, and crystalline water molecules,⁴⁸ where μ₃-O²⁻/OH⁻ are not distinguishable due to their disorder. Each vertex of the {Pu⁴⁺}₆ core is capped by a H₂O molecule (Pu–O_w = 2.688 Å) to form a nine-coordination geometry around each Pu⁴⁺. This is notable because the ionic radius of Pu⁴⁺ is smaller than that of Np⁴⁺. Due to the zwitterionic nature of AAs in the charge-neutral state, the syn–syn bridging mode of their carboxylate group is offered in both the original (H₃N⁺–CHR–COO⁻) and the deprotonated (H₂N–CHR–COO⁻) forms. This phenomenon underlies the formation of [An₆(μ₃-O)₄(μ₃-OH)₄(μ-AA⁻)_x(μ-AA)_12−x]^12−x (AA⁻: deprotonated AA) even in acidic conditions, as evidenced in the Np⁴⁺ case.⁴⁶ However, the hydrolysis tendencies of An⁴⁺ of interest should also be taken into account.

Fig. 4 Structural chemistry of M⁴⁺–AA systems reported so far, where H atoms were omitted for clarity unless specified. (A) [Th₆(μ₃-O)₄(μ₃-OH)₄(μ-Gly⁻)₆(μ-Gly)₆(H₂O)₆]⁶⁺.⁵⁷ (B) Fourier transforms of k³-weighted Np L_III-edge EXAFS spectra of [Np₆(μ₃-O)₄(μ₃-OH)₄(μ-AA)₁₂]^y+ in aqueous solutions (AA = Gly, Ala, Cys; 0 ≤ y ≤ 12).⁴⁶ (C) [Zr₆(μ₃-O)₄(μ₃-OH)₄(μ-bet)₈(κ-bet)₄(H₂O)₄]¹²⁺.⁶² (D) [Pu₆(μ₃-O)₄(μ₃-OH)₄(HDOTA)₄(H₂O)₆].^49,63 (E) [Th₂(H₂DOTA)₂(H₂O)₁₀]⁴⁻.⁶³ (F) [Th(μ-Gly)₃(H₂O)₂]_n⁴ⁿ⁺.⁵⁷ H atoms in panels (A) and (C)–(E) and terminal CH₃ groups in panel (C) were omitted for clarity. Panel (B) and (C) were reproduced from ref. 46 and 62 with permission from American Chemical Society (Copyright 2012) and Elsevier (Copyright 2012), respectively.

The scarcity of knowledge regarding AA systems is not confined solely to An⁴⁺; it also pertains to tetravalent Group 4 metal ions in the periodic table. This tendency is particularly evident in the case of Zr⁴⁺, which has undergone extensive development in this direction, though the only known hexanuclear complexes with AA are those with Gly^60,61 and its N,N,N-trimethylated variant (i.e., betaine).⁶² In the former system, the assignment of the positions of H⁺ on Gly remains ambiguous, as evidenced by the different formulas [Zr₆(μ₃-OH)₈(μ-Gly)₄(μ-Gly⁻)₄(H₂O)₈]¹²⁺ and [Zr₆(μ₃-O)₄(μ₃-OH)₄(μ-Gly)₈(H₂O)₈]¹²⁺ in the articles from the same group. The reduced number of syn–syn bridging carboxylates compared with the An⁴⁺–Gly systems described above would be ascribed to steric demand arising from the smaller ionic radius of Zr⁴⁺ (r_Zr = 0.84 Å, r_An = 0.96–1.05 Å at CN = 8).⁴⁷ In the latter case of betaine, the N-terminal of Gly was quaternarized by trimethylation to resolve the ambiguity problem of H⁺, where the zwitterionic form of betaine, (H₃C)₃N⁺CH₂COO⁻, can be maintained during complexation. As a result, preparation and structural characterization of [Zr₆(μ₃-O)₄(μ₃-OH)₄(μ-bet)₈(κ-bet)₄(H₂O)₄]¹²⁺ (bet: betaine) in conjunction with its Hf⁴⁺ analogue proved to be successful, as demonstrated in Fig. 4(C). In this study, half of the water molecules present in the preceding Gly systems were substituted with monodentate betaine, κ-bet. We have also attempted to synthesize Zr⁴⁺ hexamers with other ordinary AAs such as Ala, Val, Cys, and Leu to simulate the An⁴⁺–AAs coordination chemistry, but no crystalline deposits could be obtained.⁶² The factors that disturb the crystallization of Zr⁴⁺ hexamers with these AAs could not be fully identified. Nevertheless, there is no rationale for prohibiting the formation of the M₆O₈ complexes with AAs other than Gly for any M⁴⁺, including An⁴⁺, in aqueous solutions. As previously mentioned, the predominant formation of Np⁴⁺ hexamers with Ala and Cys was already confirmed by EXAFS.⁴⁶

In relation to AAs, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (H₄DOTA) was employed to stabilize the hydrolyzed hexanuclear complexes of An⁴⁺, [An₆(μ₃-O)₄(μ₃-OH)₄(HDOTA)₄(H₂O)₈] (An = U, Np, Pu, Fig. 4(D)),^49,63 where its triply deprotonated form, HDOTA³⁻, is involved in these An⁴⁺ hexamers. Only one out of three deprotonated carboxylates in each HDOTA³⁻ is involved in the syn–syn bridging between the neighbouring An⁴⁺ ions, while the other two are bound to An⁴⁺ in a monodentate manner. Upon initial observation, it appears that the sole protonated carboxylic group in the HDOTA³⁻ ligand is not committed to any chemical bond. However, a closer look into the structure reveals that it is hydrogen-bonded to μ₃-OH⁻, coordinating H₂O, and crystalline H₂O. These interactions contribute ultimately to the stabilization of hexanuclear clusters which has reduced number of syn–syn bridging carboxylates compared with other RCOO⁻ and AA systems described above. In contrast, neither intra- nor intermolecular interactions of any non-coordinating N atoms in the cyclen moiety of HDOTA³⁻ occur in the crystal structures of [An₆(μ₃-O)₄(μ₃-OH)₄(HDOTA)₄(H₂O)₈]. Despite the potential of Th⁴⁺ to form a hexanuclear complex with carboxylates as exemplified above, an aqueous mixture of Th⁴⁺ and H₄DOTA resulted in the formation of a dimeric complex via H₂DOTA²⁻ crosslinkers between Th⁴⁺ ions, [Th₂(H₂DOTA)₂(H₂O)₁₀]⁴⁻ = [Th(H₂DOTA)(H₂O)₅]₂⁴⁻ (Fig. 4(E)), where no olation/oxolation of Th⁴⁺ were observed presumably due to its least hydrolytic nature among the An⁴⁺ series.⁶⁴ The similar trend can be observed in the weakest intensity of the Th⋯Th interaction at R + Δ = 3.70 Å in the EXAFS spectrum of the Th⁴⁺–HCOO⁻ system (Fig. 3(C)) compared with those of other An⁴⁺ (Fig. 3(D)–(F)), indicating the least stability of [Th₆(μ₃-O)₄(μ₃-OH)₄(μ-RCOO)₁₂(H₂O)₆] among the An⁴⁺ series. A ClO₄⁻ salt of [Th(μ-Gly)₃(H₂O)₃]_n⁴ⁿ⁺ coordination polymer of Fig. 4(F) without hydrolysis of Th⁴⁺ was also yielded in a relatively acidic system at pH 1.0 as an initial condition, although it is generally difficult to identify the final pH of the mother liquor after slow evaporation of the solvent for crystal deposition.⁵⁷

To date, the previous studies on actinide hexamers have exclusively focused on structural chemistry, because molecular structures of such polynuclear species are the most distinctive feature of this class of coordination compounds. EXAFS is a valuable tool for the analysis of the structures of chemical species that are present in solution. However, through this method, only the averaged radial distributions of coordinating and related atoms around a central metal may be obtained, whereas it is hard to get any information about angular functions of atomic coordinates of interest, unless specific multiple scattering is available in a system of interest. SCXRD, in contrast, is the most powerful technique for precise structure determination, and therefore, is widely employed. However, as illustrated by our preliminary trials for Zr⁴⁺–AA systems,⁶² crystallization of a coordination compound of interest often appears to be rather challenging. Furthermore, even if crystallization is successful, the subsequent structural analysis of such an intricated compound is not always straightforward. Mainly due to crystallinity issues and remarkable disorder in atomic coordinates, the structure refinement often needs to be compromised by treating some or all non-H atoms solely with isotropic temperature factors and/or by excluding H atoms assignments. It is noteworthy that, despite the fact that a typical hexanuclear structure of [An₆(μ₃-O)₄(μ₃-OH)₄(μ-RCOO)₁₂] is basically charge-neutral, there has been no reported crystal structure composed solely of actinide hexamer units. Instead, the reported structures invariably involve salts/acids (cations: N₂H₅⁺, Na⁺, Li⁺, H⁺; anions: ClO₄⁻, NO₃⁻, Cl⁻, HCOO⁻, SCN⁻, ClO₃⁻, etc.) and/or solvent molecules. While these additional species do not directly interact with An⁴⁺, they are nevertheless likely to play important roles to hold the [An₆(μ₃-O)₄(μ₃-OH)₄(μ-RCOO)₁₂] molecule through non-covalent interactions, most typically hydrogen bonding, to construct its whole crystal structure for successful deposition of a compound of interest. Accordingly, the selection or design of a co-crystallizing salt, acid, and/or solvent should be made with the objective of facilitating the crystallization of An⁴⁺ polynuclear species and to further exploring the structural chemistry of hydrolytically-polymerized discrete An⁴⁺ coordination clusters decorated by carboxylate-based ligands.

In this context, the observed difficulty in crystallization in the AA systems can be attributed to the variable total electric charge of the M₆O₈ clusters, arising from degree of freedom of protonation/deprotonation at the terminal amino groups. Our quaternarization approach for the terminal N atom of AAs to immobilize the positive charge on it would be straightforward to resolve this issue even in An⁴⁺–AA systems.⁶² Indeed, N,N,N-trimethylated AA derivatives have already been prepared as bis(trifluoromethylsulfonyl)imide (Tf₂N⁻) salts,⁶⁵ while the original aim of that work was development of a new class of AA-based ionic liquids. Although deprotonation from such AA-derivatives to liberate them from Tf₂N⁻ counter anion is still required for utilization of such zwitterionic betaine-type AAs, exploration of the structural chemistry of An⁴⁺ hexamers with AAs could be anticipated in such a manner.

To the best of our knowledge, the sidechains of Ala (R = –CH₃) and Cys (R = –CH₂SH) play only a bystander role during the formation of Np⁴⁺ hexamers in aqueous solutions (Fig. 4(B)).⁴⁶ Due to the limited exploration of An⁴⁺–AA systems, the impact of the sidechains of AA on the coordination chemistry of An⁴⁺ remains to be elucidated. This is particularly evident for acidic AAs, such as Glu (R = –C₂H₄COOH) and Asp (R = –CH₂COOH), that comprise carboxylates within their sidechains. In the case of peptides and proteins, in which the carboxylic groups of AAs on the backbone are no longer available for coordination after their condensation with the –NH₂ of the neighbouring AA to form peptide bonds, the presence of carboxylic groups on the sidechains increases its significance. As a matter of fact, the EXAFS study by Daronnat et al. reported that Pu⁴⁺ forms a Pu₆O₈ cluster after binding to a wild-type calmodulin peptide, CaMWT (DKDGDGYITTKE).⁶⁶ This finding was confirmed by Pu⋯Pu interactions at R + Δ = 3.8 Å and 5.2–5.3 Å, which are representative signatures of the An⁴⁺ hexamers (see Fig. 3(C–F) and 4(B)). Subsequent molecular dynamics simulations suggested that Pu⁴⁺ can be solvated by H₂O molecule(s) even after being captured by the coordination site of CaMWT. This process enables the initiation of the hydrolysis of Pu⁴⁺ to form the Pu₆O₈ structure. In contrast, this phenomenon was not observed when another calmodulin peptide with a mutation, CaME (DKDGDGYIEAAE), was employed. In this case, no H₂O was found to enter the coordination sphere of Pu⁴⁺. Despite the lack of comprehensive picture depicting the final accommodation of the Pu₆O₈ core within CaMWT, this work clearly represents importance of sidechains of AAs in the An⁴⁺ coordination chemistry. Herein, interconnections between the fundamental coordination chemistry of small molecular structures of An⁴⁺ with organic substances and extended biologically-relevant systems such as peptides and proteins have been established.

An An⁴⁺ hexanuclear complex commonly contain an An₆O₈ core unit, where all An⁴⁺–O²⁻, An⁴⁺–OH⁻, and An⋯An distances follow those in the Fm3̄m fluorite-like AnO₂ crystalline phases (U–O: 2.368 Å, U⋯U: 3.866 Å in UO₂; Th–O: 2.424 Å, Th⋯Th: 3.958 Å in ThO₂).³⁸ Therefore, a minimal AnO₂ crystalline unit can be postulated to be isolated within a hexanuclear complex, wherein all twelve edges of the AnO₂ unit cell are occupied by RCOO⁻ to inhibit further hydrolytic interactions of incoming An⁴⁺ to μ₃-O²⁻/–OH⁻. The decoration of the surface of the An₆O₈ core with RCOO⁻ efficiently terminates the crystal growth into bulk AnO₂, and eventually prohibits its deposition. Indeed, the presence of RCOO⁻ enables the preparation of aqueous solution samples with An⁴⁺ concentrations as high as ≥10⁻² M, as exemplified in Fig. 3 and 4. This concentration level is significantly higher than that of the original aqueous solubility of An⁴⁺ (e.g., ≲10⁻⁸ M at pH > 4 for An = Pu), which is expected from their hydrolytic nature.⁶⁷ This finding has critical implications for the concept and strategy for geological disposal of nuclear waste. In relation to this subject, the CEA group has investigated the growth of the PuO₂ colloidal nanoparticles from the perspective of H/D kinetic isotope effects (KIE). Formation of the Pu₆O₈ cluster occurs during the early stage of the reaction, followed by an O–H bond cleavage (probably at μ₃-OH⁻ of the hexamer) as a rate-determining step.⁶⁸

Now, a fundamental question emerges from these observations; does An⁴⁺ undergo further hydrolytic oligomerization from the An₆O₈ unit to ultimately form AnO₂ nanoparticles? If so, how? This mechanistic matter is critically responsible for the solubilization of An⁴⁺, which is generally believed to be immobilized as sparingly soluble AnO₂ phase. Furthermore, it is important in evaluating actinide transport in the geosphere following the disposal of nuclear waste in deep underground repositories. While there have been DFT calculations that have simulated tri-, tetra-, hexa-, and 16-nuclear hydrolyzed Pu⁴⁺ clusters decorated by CH₃COO⁻, a plausible oligomerization process is yet to be concluded through experiments.⁵¹ Fig. 5 summarizes An⁴⁺ oligomer structures that have been characterized to date. The Pu₁₆O₂₃,⁶⁹ Pu₂₂O₃₂,⁶⁹ and Pu₃₈O₅₆ ^69–71 clusters deposited from aqueous mother liquors were identified by X-ray crystallography, where Cl⁻ was employed instead of carboxylates to afford higher nuclearities of Pu⁴⁺ in these oligomers. However, no clear evidence of oligomeric nanostructures other than the Pu₆O₈ clusters in the reaction process was obtained at this time, implying either the absence or minor contribution of the larger oligomers during the formation of the PuO₂ nanoparticles.⁷² In the case of U⁴⁺, Falaise et al. obtained a hydrolysed 38mer after solvothermal treatment under controlled hydrolytic conditions in THF.⁷³ This U₃₈O₅₆ cluster bears a striking resemblance to the chloro-decorated Pu⁴⁺ 38mer described above, while a mixed ligand system comprising PhCOO⁻ and Cl⁻ has been strategically employed to regulate the growth of UO₂. Additionally, Mazzanti's group detected more diverse U⁴⁺ oligomers with 6, 13, 16, 24, and 38-nuclearities in the PhCOO⁻–Cl⁻ mixed ligand systems under the presence of a limited amount of H₂O in non-aqueous solvents such as CH₃CN and pyridine.⁷⁴ The 10, 12, and 22mers of U⁴⁺ were also suggested to occur in the reaction mixture. In general, the detection of some oligomers with specific numbers of metals should be regarded as merely a “snapshot” and their presence should not be overinterpreted. On the other hand, Pu⁴⁺ has been observed to exhibit a greater tendency for colloidal formation and migration,⁷⁵ as evidenced by the 1.3 km Pu transport observed at the Nevada nuclear test site.⁷⁶ Therefore, it is highly probable that U⁴⁺ and Pu⁴⁺ undergo distinct polymerization processes. It is worthwhile that, in most cases, the An₆O₈ core unit of the smallest unit of the fluorite-like crystalline AnO₂ are included in the reported An⁴⁺ hydrolysed oligomers with the higher nuclearities as highlighted in Fig. 5. A comprehensive understanding of the tendency of olation and oxolation of An⁴⁺ remains elusive, particularly in the context of variation among different actinides.⁷⁷ Further investigation in this area is necessary to gain a more comprehensive understanding of these phenomena.

Fig. 5 Previously identified An⁴⁺ (An = U and/or Pu) oxo/hydro oligomers relevant to further polymerization and nanoparticle formation. Numbers in bold indicate the number of actinides within each oligomer. Only species relevant to aqueous chemistry are depicted. The inset at the top right shows the structure of {An}₃₈ core, with a single hexamer unit highlighted in yellow. The figure is based on the works by Nyman,⁵⁹ Hixon,⁶⁹ Soderholm,⁷⁰ Loiseau,⁷³ Wilson,⁷¹ Virot,⁷² and Mazzanti.⁷⁴

Besides the mechanistic features described above, it is also mandatory to compile chemical thermodynamic data of An⁴⁺ hydrolysed oligomers, particularly those of hexamers, to quantitatively and universally comprehend the phenomena occurring within the aqueous system of interest. This encompasses the behaviour of An⁴⁺ in relation to additional concerns, such as adsorption and migration behaviour of An⁴⁺ in natural environments related to the nuclear waste disposal. The stability constants of the An⁴⁺ oligomers exemplified above represent the most fundamental data necessary to predict the predominance of each species under specific conditions. In particular, the formation of an n-nuclear An⁴⁺ cluster is promoted in proportion to the n-th power of its concentration, more correctly “activity”, in accordance with the mass action law. Therefore, simulating the solution chemistry of An⁴⁺ at micro- or nano-molar levels under the presence of carboxylate-based ligands is of crucial interest. However, to the best of our knowledge, virtually no research work has been done in this area, in contrast to extensive body of work on structural chemistry. We have previously established the stability constants of [Np₆(μ₃-O)₄(μ₃-OH)₄(μ-RCOO)₁₂] (R = H, CH₃) in conjunction with the related monomeric species, [Np(RCOO)(OH)₂]⁺, which functions as a precursor for the Np⁴⁺ hexamer as outlined below:

6 Np⁴⁺ + 12 RCOO⁻ ⇄ [Np₆(μ₃-O)₄(μ₃-OH)₄(μ-RCOO)₁₂] + 12 H⁺ (1)

Np⁴⁺ + RCOO⁻ ⇄ [Np(RCOO)(OH)₂]⁺ + 2 H⁺ (2)

R = H, log β_6,12,−12 = 42.7 ± 1.2 and log β_1,1,−2 = 2.51 ± 0.05; R = CH₃, log β_6,12,−12 = 52.0 ± 0.7 and log β_1,1,−2 = 3.86 ± 0.03, where log β_n,l,m is the logarithmic gross stability constant of a Np⁴⁺–RCOO⁻–H⁺ ternary complex with stoichiometries of these components denoted by n, l, and m, respectively. Based on these thermodynamic data, the speciation diagram for each system was successfully plotted as illustrated in Fig. 6(A) and (B),⁴⁶ where predominant formation of the Np⁴⁺ hexamers is predicted to start even under acidic conditions below pH ∼ 2. In Fig. 6(C), pH dependencies of Np⁴⁺ solubility under the presence of HCOO⁻ or CH₃COO⁻ under different concentration levels (10 mM, 1 M) were calculated from the above stability constants plus hydrolysis data of Np⁴⁺ available in the literature,⁶⁴ and overlaid on that of Np⁴⁺ hydrous oxide comprehended by Neck and Kim.⁶⁷ Note that the aqueous solubility of Np⁴⁺ is significantly enhanced especially in the acidic region after loading RCOO⁻, while these conditions have been arbitrarily selected for simulation. No thermodynamic data are available for any An⁴⁺–AA systems even today despite its higher biological relevance and stronger complexation tendency with metal ions including An⁴⁺. Further research in the field of thermodynamics is necessary to ascertain the significance of actinide oligomers in environmental contexts.

Fig. 6 Speciation diagrams of Np⁴⁺–RCOO⁻ systems (R = H (A), CH₃ (B))⁴⁶ as a function of pH together with logarithmic solubility of Np⁴⁺ in aqueous solutions (C) under absence (black)⁶⁷ and presence of RCOO⁻ (R = H (blue), CH₃ (red); [RCOO⁻] = 10 mM (dashed), 1 M (solid))⁴⁶ at different pH. Panel (A) and (B) were reproduced from ref. 46 with permission from American Chemical Society (Copyright 2020). Panel (C) was adapted from ref. 67 with permission from De Gruyter Brill (Copyright 2001).

3. Actinide and peptide

The concept of employing peptides to facilitate the recovery of metals, or at the very least to synthesize metal–peptide complexes, traces back to the early 1960s.⁷⁸ The majority of proteins involved in essential biochemical processes depend on metal cofactors to execute their functions. Therefore, preliminary research on metal-binding proteins frequently relied on metalloprotein and metalloenzyme studies to gain insights from nature's wisdom. In this context, the interactions between lanthanides/actinides and peptides have received much less attention, primarily due to the absence of any metalloprotein that utilize lanthanide/actinide, until Ln-dependent metalloenzyme was first discovered in 2011.⁶

Glutathione (GSH) is one of the simplest peptides consisting of just three amino acids (Glu, Cys, Gly) and known to be ubiquitous and found in all cells of the body. Kretzschmar et al.⁷⁹ conducted a study on the interaction between GSH and uranium(VI). The primary inquiry concerns the manner in which U(VI) binds with GSH. It has been determined that this binding occurs through the involvement of a carboxylic group, rather than a thiol group. This finding is consistent with the earlier study by Fahmy et al.,⁸⁰ who employed isothermal titration calorimetry (ITC) to investigate the interaction between the two substances. Furthermore, Kretzschmar et al. observed the reduction of U(VI) to U(IV) in the presence of GSH via an intermolecular mechanism in an aqueous medium in vitro. This process induced the formation of nanocrystalline, mixed-valence uranium oxide particles. Kretzschmar et al. also studied the interaction between U(VI) and glutathione disulfide (the disulfide complex of two glutathione molecules, GSSG) to observe the formation of the insoluble, low-mobility U(VI)–GSSG complex.⁸¹ Fahmy et al.⁸⁰ studied the detoxification of uranium by GSH, using anaerobically grown Lactococcus lactis as a model organism. Their data suggest that the primary detoxification mechanism involves the intracellular sequestration of carboxyl-coordinated U(VI) into an insoluble complex with GSH, which is presumably related to the formation of U(VI)–GSSG or U(IV).

The interaction between short tripeptide like GSH and U is significant in the context of redox reaction, rather than due to its binding through one or two functional groups. Usually a longer peptide (>10 amino acids) is required to observe more specific binding patterns. The structural characteristics of calcium-binding proteins, particularly the EF-hand motif, have served as a model for the development of lanthanide-binding peptides, because of the similarity in the size of ionic radius of Ca²⁺ and Ln³⁺. The binding of Ln³⁺ by calmodulin–peptide has been thoroughly studied,⁸² Pu⁴⁺ interactions with two variants of calmodulin–peptide have been also studied,⁶⁶ and recently such study has been extended to lanmodulin peptides⁸³ and even those with the reversed sequences⁸⁴ (Fig. 7). So-called lanthanide-binding tags (LBT) with high and selective recognition of lanthanides are also known for more than 20 years,^85–87 which was later extended to Am³⁺-binding research.⁸⁸ Jeanson and coauthors designed An(III) and An(IV) binding peptides from a “scratch” and made systematic investigation, though their strategy was primarily focused on utilizing acidic amino acids exclusively.^89,90

Fig. 7 The optimized structures of Eu³⁺-bound reversed lanmodulin EF Hand 1 peptide obtained by DFT calculations with dispersion corrections and LC-ECP (six 4f electrons incorporated into the frozen core) applied on Eu³⁺. Green sticks, orange ball, blue sticks depict the peptide, Eu³⁺, three coordinating water molecules, respectively. Gray sticks show the previously-calculated structure⁸⁴ using MD simulations based on 12-6-4 LJ potential on Eu³⁺. Two structures (DFT and MD) are superimposed to highlight their agreement.

Uranium (and thorium) is perhaps one of the most intensively studied elements among lanthanides and actinides for its binding with peptides,^91–95 due to their affordability and minimal radioactivity, which facilitates their handling in laboratory settings. However, these elements may not be the most intriguing for study in terms of recovery and separation because they are the most abundant actinide elements in nature. Conversely, their abundance in nature has led to significant research interest in their detection. The potential health implications of human exposure to uranium encompass both radiological and chemical toxicity.⁹⁶ The average U concentration in drinking water varies significantly among different regions and countries,^97,98 and the presence of U in aquifers has the potential to pose health concerns mainly because of its chemotoxicity. The development of its in situ measuring technique is awaited. The development of peptide-based sensors for U/Th detection has emerged as a prominent research area in recent years.^99–101 Phosphorylation of peptide is frequently employed to enhance their binding affinity to actinides.^102–105 However, this process transforms the peptide into a mere scaffold, prompting the question of whether the use of noble materials like peptides is truly essential when their sole function is to serve as the backbone that hold the phosphoryl groups hands for the capture of metal ions. In an alternative approach, His-decorated phenanthroline diimide was utilized for the recovery of Am³⁺.¹⁰⁶ In this instance, the incorporation of amino acids was intended to enhance solubility and they are not involved in metal-binding. Some prominent chelators, including DOTA (dodecane tetraacetic acid), EDTA (ethylenediaminetetraacetic acid), and NTA (nitrilotriacetic acid) are classified as aminopolycarboxylic acids. These chelators share Gly as a parental complex. The complexation of these chelators with trivalent actinides is a subject of intensive research in the direction of separation of lanthanides and minor actinides.¹⁰⁷

Radiopharmaceuticals are also complexes that contain a peptide segment in their structure, as well as a separate metal-capturing chelator component. In the case of radiopharmaceuticals, however, the peptide portion plays a distinct role in binding with a receptor at its extracellular domain, thereby inducing a conformational change in the receptor and activating its intracellular domain. For the metal-capturing component, a strong chelator such as DOTA is typically selected. In recent years, a novel research domain has emerged that utilizes these chelators for radiotherapy. ²²⁵Ac-based radiopharmaceuticals have gained increased attention for its application in α-particle therapy, a treatment modality that has been shown to be more effective in the destruction of tumour cells when compared to β-emitting radionuclides.¹⁰⁸ In this particular context, as well, phosphorylation has been identified as a promising strategy to enhance the binding affinity of Ac³⁺.^109,110 It should be noted that the coordination chemistry of Ac³⁺ is still rather poorly understood,¹¹¹ and studies on its daughter products, such as Fr and At, are even more scarce. It is frequently assumed that Ac³⁺ persists in binding to the chelator subsequent to its decay to its daughters. However, this is exceedingly improbable, given that Fr⁺ is the largest cation in the periodic table. It is imperative that further investigation be conducted into the coordination chemistry of these elements (Ac, Fr, At), which have received the least attention in the periodic table so far.

Now, we will shift the discussion to an entirely different topic; the implementation of computer chemistry in this research domain. While the application of computer chemistry, such as density functional theory (DFT), has been extensively implemented in the field of general actinide chemistry, its application in the context of actinide interaction with peptide or protein has been extremely scarce. However, this emerging field has undergone significant development in the past decade, a topic which will be discussed in the remainder of this section. Due to smaller size of peptides in comparison to proteins, they offer greater potential for computer simulation, and the application of computational chemistry in this field is expected to become more widespread in the future. Quantum chemical calculations (e.g. DFT) and classical molecular dynamics (MD) simulations can be employed to study peptide structures and their metal bindings. Each method addresses different aspects and has different strengths. Quantum chemistry is an ab initio method that provides accurate electronic and geometric structures of peptides. In contrast, classical MD simulation is based on empirical parameters and is more suited for simulating dynamic behaviour and conformational changes of peptides. Peptides are known for their structural flexibility, which complicates the prediction of their structures, including those in metal-bound states. Peptide structure optimization frequently lacks any initial structures to begin with. In such cases, the use of DFT can prove challenging in terms of identifying the global energy minimum with reasonable computational cost. The employment of a more expeditious and dynamic approach, such as classical MD simulations, is often a more suitable alternative. There was great advent in this field in the last decade largely due to the parameterization of M³⁺ and M⁴⁺ ions using the 12-6-4 Lennard-Jones-type nonbonded model by the group of Kenneth Merz.^112–114 Their parametrization included exotic ions such as Th⁴⁺, U⁴⁺, and Pu⁴⁺. The structures of Eu³⁺-bound peptide obtained by using their 12-6-4-type potential is comparable to the DFT-optimized structure, which prove their validity (Fig. 7). Hay and coworkers extended this potential (parametrized for water coordination) to the protein system to better reproduce the binding energy for M³⁺-binding peptides.¹¹⁵ Not all MD programs are compatible with 12-6-4-type potentials, and the widely-used GROMACS software cannot handle this type of potentials, which is a significant setback to the research in this direction. In an another effort, the group of Stefan Grimme has recently extended robust atomistic generic force field GFN-FF to lanthanide and actinide biomolecule system and claimed that the structures they obtained are almost comparable to those using DFT.¹¹⁶ Another interesting and important development by Grimme and his coworkers is the development of composite methods which he calls “Swiss army knife” and utilizes relatively small basis sets and special corrections to achieve high accuracies at a fraction of the computational cost of a calculation approaching the basis set limit. In the realm of computational chemistry, intermediate methods that straddle the divide between quantum chemistry (e.g. DFT) and classical mechanics include the QM/MM approach and the FMO (fragment molecular orbital) method (Fig. 8). These methods possess two key advantages. Firstly, they are significantly less expensive than purely quantum chemistry-based methods. Secondly, they are more accurate in energetics than purely classical mechanics-based approaches. We have recently successfully applied FMO methods in various lanthanide/actinide-containing biological system with the help of group of Yuji Mochizuki.^25,117,118

Fig. 8 Schematic illustration of different computational approaches. (A) Conventional methods (QM or MM) apply a single level of theory to the entire system. (B) QM/MM treats a key region (red) with QM, and the remainder (green) with MM. (C) Fragment Molecular Orbital (FMO) theory divides the system into fragments, calculating energy of each fragment and fragment pairs using QM to reconstitute the energetic of the whole system.

4. Actinide and protein

A preliminary analysis of the existing literatures on actinide/lanthanide interactions with protein reveals the presence of three predominant research categories. The initial category pertains to the utilization of proteins for the recovery and/or separation of these elements. The second type of research entails the investigation of the potential of actinide to interact with proteins relevant to humans, and the subsequent impact on human health, particularly in the context of accidental exposure (e.g. nuclear accident). The third category of research has emerged within the last decade. The focus of those studies is on the protein/bacteria present in nature that are capable of utilizing lanthanide or actinide in their enzymatic activities. These three types of research are interconnected and frequently refer to analogous types of proteins or domains. Nevertheless, we discuss these subtopics independently.

A number of attempts have been made to recover hexavalent uranium (UO₂²⁺) using protein-based materials.^119–122 However, such technology remains ambitious for practical application considering the relatively low market price of uranium (merely ∼10 times that of copper).¹²³ In practice, there are much more economic approaches for the recovery of uranium from seawater,^124–127 though their economic viability still remains suboptimal, necessitating ongoing technological development. Nevertheless, in scenarios where the primary objective is the recovery of Ln/An from wastewater to avert environmental contamination, cost considerations become a secondary issue, and protein-based materials eventually emerge as a viable alternative.^128,129 It also remains a significant challenge to separate Ln and An or amongst themselves, especially in the nuclear industry, for which protein-based materials could be utilized.^130,131 In the context of metal ion recovery and isolation from a matrix or from wastewater for the purpose of bioremediation, the utilization of abundant materials such as surface layer (S-layer) protein is advantageous due to the heterogeneity of these materials, which does not pose a significant problem.¹²⁸ On the other hand, in scenarios where the objective is mutual separation of metal ions, the homogeneity of the material becomes a central concern, necessitating the purification of the material. In general, peptide is more appropriate for such purpose rather than protein. This is because only few amino acid residues are anyway committed to metal-binding. Consequently, in the absence of a significant breakthrough in the research, such as the confirmation of bulk, biologically mass-producible proteins that are effective in the separation of actinides and/or lanthanides, further research in this area appears to be challenging. In this particular context, alcohol dehydrogenase (ADH) enzymes have been observed to exhibit the capacity to utilize lanthanides and actinides, and even demonstrate a degree of discrimination among them. This issue will be addressed subsequently in this section.

With regard to the interaction between actinide and protein in human-related scenarios, Creff et al.¹³² provided an excellent comprehensive review on this topic, which summarizes previous studies conducted since the Manhattan project. Creff et al. describe that primary tasks of previous researches can be classified into three categories; first the identifications of the proteins that are relevant to human-related scenarios, second the investigations on the structures and the affinities of the An-binding proteins, and third to study the impact of uptake of An-bound proteins. Serum proteins have been extensively employed to study its affinity to actinides, as they play crucial role in facilitating metal transportation within the human body, suggesting a potential for involvement in actinide transport processes. This includes studies of actinide interactions with albumin,¹³³ transferrin,^134–136 ferritin,^137,138 and hemoglobin.¹³⁹ The collective findings of these studies indicated high affinity between actinide and proteins, with the potential binding site of actinide being either specific or non-specific (Fig. 9). In vivo studies employing rats after implantation with depleted uranium fragments have demonstrated U accumulation in their kidneys and bones. However, the study also exhibited a minor increase in serum U levels, attributable to rapid urinary excretion.¹⁴⁰ Therefore it is important to note that while certain proteins possess a high capacity to incorporate actinides, this does not inherently signify that those proteins function as actinide accumulators within the human body. On the other hand, it has been hypothesized that the process of bone turnover involving Th(IV) and Pu(IV) is associated with the presence of hyperphosphorylated proteins, such as osteopontin.¹⁴¹ Phosphorylated proteins are generally identified as strong actinide binders as in the case of phosvitin^142,143 and bovine milk protein.¹⁴⁴ This is also one of the reasons why phosphorylation is frequently used as a strategy to increase the affinity of peptides towards lanthanides and actinides, as we discussed in the preceding section. Another protein that has been extensively studied in relation to lanthanide and actinide binding is calmodulin, a calcium-binding messenger protein. It has been demonstrated that calmodulin can accommodate up to four Ln³⁺ (or An³⁺) ions.¹¹⁷ Cotruvo et al. have discovered calmodulin-like protein which has high selectivity for Ln³⁺ (and An³⁺) and named it as lanmodulin.^7,145 However, the actinide–calmodulin interaction appears rather irrelevant in connection to human health issues, and its high affinity is discussed and utilized in a separate setting. Overall, there are still many open questions in this field of research. For instance, the genotoxicity of uranium has been demonstrated not to be necessarily associated with U–protein interaction. Rather, U genotoxicity has been suggested to be more associated with DNA strand breaks and chromosome aberrations.⁹⁶ The issue of actinide toxicity in the human body is not a simple problem that can be attributed to the interaction with several particular proteins. Further comprehensive research is needed to elucidate the mechanisms by which this toxicity occurs. At the same time, it is also imperative to have parallel studies on decorporation agents of actinides to prepare for accidental exposure of humans.^146–148

Fig. 9 The structures of plutonium(IV)-bound proteins from molecular dynamics (MD) simulations^136,137 based on 12-6-4-type Lennard-Jones potentials on Pu⁴⁺. The left-hand side of the figure displays Pu⁴⁺-bound ferritin, a single L chain of horse ferritin (PDB reference 1AEW) with six Pu⁴⁺ ions present. The right-hand sides of the figure displays Pu⁴⁺-bound transferrin, a transferrin (PDB reference 1FCK) incorporating two Pu⁴⁺ ions. In both figures, protein structures are depicted as green ribbon and Pu⁴⁺ ions as red balls. Waters and other ions (Na⁺, CO₃²⁻, etc.) are omitted for clarity. Note that in the case of ferritin, Pu⁴⁺ ions are bound to the carboxylic groups of random acidic residues (Asp, Glu) in a non-specific manner, whereas in the case of transferrin two Pu⁴⁺ ions are stably accommodated in the iron-binding sites of transferrin with a closed conformation.

The third category of research constitutes an emerging new field of science, which is concerned with the proteins (and enzymes) present in the nature that are capable of accommodating lanthanide or actinide ions. Trivalent lanthanides were long believed to lack any essential biological function. However, in 2011, Kawai and coauthors revealed the catalytic role of trivalent lanthanide ions in the enzyme methanol dehydrogenase (MDH).^6,149,150 Later, the growth of the Methylacidiphilum fumariolicum strain SolV, isolated from volcanic mud water in Italy, was found to be strictly dependent on the concentration of Ln³⁺ ions.¹⁵¹ It was even confirmed that XoxF-type MDH can discriminate amongst different lanthanides.¹⁵² In XoxF-type MDH, lanthanide binding to the cofactor pyrroloquinoline quinone (PQQ) was found to transition from a chelate to an unidentate conformation as the lanthanides transition from lighter to heavier elements. This observation was made through the use of molecular dynamics (MD) simulations.¹¹⁸ The enzymatic activity exhibited by XoxF-type MDH, which is exclusive to lighter lanthanides, was identified as the underlying cause of this phenomenon (Fig. 10). These discoveries expanded the significance of Ln³⁺ ions in biochemistry and in bacterial metabolism. Recent findings have even confirmed that active microbial methanol oxidation in the ocean by MDH is almost entirely Ln-dependent despite the fact that Ln exist only in trace concentrations,¹⁵³ and that Ln–MDHs are far more broadly distributed than the Ca–MDHs. In the field of biology, it is common to observe examples where the life of organism is dependent on trace elements, and these elements become toxic at higher concentrations. The prevalence of Ln-dependent MDH in natural environments suggests the potential for a novel and hitherto unrecognized role for lanthanide (and potentially actinide as well) in a complexity that is both novel and hitherto unappreciated. In this context, the discovery of actinide-dependent MDH was not unexpected.¹⁰ Consequently, the hypothesis that actinides played a certain role in the evolution of primitive metabolic processes (as we discussed in Introduction) may not be entirely dismissed. Despite that actinide-dependent MDH has been confirmed exclusively for heavy actinides Am(III) and Cm(III) in a laboratory setting, given the presence of a high H₂ concentration in the Hadean earth's atmosphere (some sources refer to this as large as ∼0.1 bar), the possibility of Pu(III) being present, along with their association with MDH, remains a possibility. Indeed, it is hypothesized that Pu in Oklo (Gabon) from natural reactor in reaction zone 16 existed as Pu(III).¹⁵⁴ The isolation and identification of protein lanmodulin⁷ revealed its capacity to utilize light to heavy actinides, including Ac(III),¹⁵⁵ Am(III) and Cm(III).^{145,156–158} A recent study revealed that a specific type of lanmodulin from Hansschlegelia quercus exhibits sensitivity to the size of Ln³⁺.¹⁵⁹ This finding is analogous to the discovery previously made for Ln-dependent MDH,¹⁵² though in the case of MDH the effect of the size of Ln³⁺ ions appears more critically in their structures by switching the coordination mode of cofactor pyrroloquinoline quinone (PQQ) (Fig. 10). In comparison to its Ca²⁺-binding counterpart calmodulin, lanmodulin exhibits a significantly shorter sequence, containing only half as many residues in its EF hand loop (12 or 13 for lanmodulin, whereas 24 or 25 for calmodulin). The results of evolutionary studies are awaited to ascertain whether these two proteins are genetically related and whether they have undergone an increase or decrease in size and complexity through processes such as gene duplication and fusion. Such study may provide preliminary evidence that shorter Ln/An-bound proteins may have existed earlier in evolution than their Ca²⁺-bound counterparts, and may lend further credit to the hypothesis that primitive proteins and enzymes have utilized Ln and/or An. A recently discovered lanthanide-binding protein, Lanpepsy, has been found to possess three to four binding sites for Ln³⁺ ions.¹⁶⁰ This finding provides further evidence for the prevalence of lanthanide-dependent life.

Fig. 10 The structures of La³⁺- and Yb³⁺-bound methanol dehydrogenase (MDH, XoxF-type) from molecular dynamics simulations.¹¹⁸ On the left- and right-hand sides are La³⁺- and Yb³⁺-bound MDH, respectively. The top views show global conformation of the metalloenzyme whereas the bottom views show the central metal ion and its vicinity including cofactor pyrroloquinoline quinone (PQQ). Only in the La³⁺-bound MDH, PQQ coordinates to metal ion in chelate binding mode thereby allowing nucleophilic attack of the methanol oxygen on PQQ.

5. Summary and perspectives

This Perspective presents a comprehensive review of the interplay between actinides and biomolecules. A thorough review of actinide coordination chemistry reveals a complex landscape of interactions of actinides with carboxylates, amino acids, peptides, and proteins. The formation of stable oligomeric complexes, particularly the hexanuclear An⁴⁺ clusters, underscores the potential for actinides to influence their solubility, stability, and transport in the environment. The observed preference for syn–syn bridging carboxylates, in conjunction with the influence of hydrolysis on complex formation, suggests the existence of specific pathways for the assembly of more complex structures including AnO₂. A more extensive study of the potential transport route and the mechanism of An nanoparticles in the vicinity of a natural nuclear reactor are necessary to elucidate the roles of early actinides in primitive life. Such studies are also important in the context of nuclear waste disposal.

The emerging field of actinide-dependent proteins, as exemplified by lanthanide-dependent methanol dehydrogenase and lanmodulin, may supports the notion that lanthanides and actinides were not merely passive participants in early metabolic processes, but could have been actively incorporated into the catalytic role in early life. The discovery of these enzymes challenges the long-held assumption that life is exclusively reliant on a limited set of metal cofactors and opens the possibility that lanthanide (or actinide)-based metalloenzymes may have played a crucial role in the earliest stages of evolution. Further phylogenetic analyses are necessary to confirm that lanthanide (or actinide)-dependent enzymes possess in fact ancestral features and that the calcium-dependent versions evolved later, as discussed elsewhere.¹⁶¹ The observation that some of these proteins exhibit selectivity for different lanthanides and even actinides, and that this selectivity is linked to their ionic radii and coordination preferences, underscores the potential for fine-tuning of metabolic pathways through subtle variations in metal composition. Additionally, there is little knowledge regarding the interactions between tetravalent actinide and proteins, despite the significance of this oxidation state in geologic implications (as exemplified by the formation of An⁴⁺ polymers). Addressing this knowledge gap is imperative.

Significant challenges remain in fully evaluating the validity of the nuclear geyser model. While we have presented a compelling case for the chemical feasibility of actinide-driven abiogenesis, direct evidence linking natural nuclear reactors to the origin of life remains elusive. Furthermore, the inherent complexity of prebiotic systems necessitates a multidisciplinary approach that integrates geochemistry, radiochemistry, biochemistry, and computational modelling. Ultimately, resolving the question of whether actinides played a significant role in the origin of life will require a sustained and collaborative effort involving researchers from diverse disciplines. Such investigations will not only provide a deeper understanding of the fundamental processes that gave rise to life on earth, but also a more informed approach to the high-level radioactive waste disposal in the geosphere.

Author contributions

S. T.: Conceptualization, investigation, funding acquisition, project administration, supervision, writing—original draft, writing—review and editing. K. T.: Conceptualization, investigation, funding acquisition, project administration, supervision, writing—original draft, writing—review and editing. All authors have read and agreed to the published version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Acknowledgements

We thank all colleagues at SciTokyo, HZDR, and other associated institutes. This Perspective was supported in part by Grant-in-Aid for JSPS Fostering Joint International Research (B) (JP20KK0119), Grant-in-Aid for Scientific Research (B) (JP24K01398), and International Collaborative Research (JP24KK0109).

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