Introduction to Quantum bio-inorganic chemistry

Bio-inorganic chemistry focuses on the interactions of metals with organic species, particularly on metalloenzymes and biomimetic compounds. The study of bio-inorganic chemistry with the tools of quantum chemistry is commonly known as quantum bio-inorganic chemistry. The idea of using the tools of quantum chemistry to study complex bio-inorganic chemistry has been around since computers allowed the first practical computations. Nowadays, the field has come far, with modern studies of full atomistic models of, e.g. large metalloenzymes, commonplace, employing not only methods based on density functional theory but also wave function theory.

In this themed collection, originally organized in conjunction with the 6th Quantum Bio-Inorganic Chemistry meeting in 2023, we have gathered 30 articles on the topic, published in PCCP and Dalton Transactions. The articles are as diverse as the field itself, on sub-topics such as computational methodology (including new coupled-cluster- (https://doi.org/10.1039/D4CP01500B) and multiconfigurational-based approaches (https://doi.org/10.1039/D4CP01297F)), theoretical spectroscopy (e.g., Mössbauer (https://doi.org/10.1039/D4CP00431K) and vibrational spectroscopy (https://doi.org/10.1039/D4CP01307G)), detailed studies into metalloenzymes (such as nitrogenase (https://doi.org/10.1039/D4DT00937A) and lytic polysaccharide monooxygenase (https://doi.org/10.1039/D3DT04275H)), bioinspired and biomimetic coordination complexes as they relate to either catalysis (e.g., hydrogen evolution reaction (https://doi.org/10.1039/D4DT03507K)) or metals in medicine (such as Zn complexes (https://doi.org/10.1039/D4DT01353K)). Importantly, many of the articles feature not only quantum chemical computations but also joint experimental–theoretical investigations. Below, we highlight three works that are representative of the collection.

Theoretical spectroscopy plays an important role in quantum bio-inorganic chemistry, being in some ways the most direct way of connecting models of molecular and electronic structure to the results of experiments. Transition metal complexes, whether part of metalloprotein active sites or bioinspired synthetic complexes, however, present considerable challenges to the accurate calculations of theoretical spectra, especially when probing electronic states involving first-row transition metal d-orbitals and core-valence transitions. Boydas and Römelt (https://doi.org/10.1039/D4CP01900H) contribute to the current collection by calculations of ligand K-edge and metal L-edge X-ray absorption spectra of transition metal (Co,Fe,Mn) phthalocyanines. Ligand (N,F) K-edge spectra are found to be very well reproduced by a time-dependent density functional theory (TDDFT)-based protocol while the metal L-edge spectra prove highly challenging to reproduce, despite the use of a state-of-the-art multireference wave function strategy. The authors speculate whether the disagreement arises due to missing correlation effects due to necessary limitations of active orbital spaces used for these conjugated systems or possibly from missing interface and bulk environmental effects.

Binding of dioxygen is often the first step in catalytic cycles of metalloenzymes and could lead to a diversity of reaction mechanisms and final products. Often, the binding of O₂ invokes a metal-to-O₂ single-electron transfer to generate a metal-superoxo species, although Bertozzi, Solomon, and co-workers recently reported on the formylglycine-generating enzyme¹ in which dioxygen binds as dioxygen, not superoxo. In this themed collection, Ye and co-workers (https://doi.org/10.1039/D4CP02915A) investigated the binding of O₂ to an Fe(II) and a Co(II) complex based on complete active space self-consistent field (CASSCF) and N-electron valence state second-order perturbation theory (NEVPT2) calculations. Through this approach, they could obtain both the M(III)–superoxo and M(II)–dioxygen complexes, which confirmed the preferred formation of a metal–superoxo species. This process was shown to be the result of an avoided crossing of two diabatic curves. With this in hand, they analysed the processes in terms of spin-density and valence-bond analyses and studied the performance of density functional theory (DFT) methods. The authors argue against using broken-spin solutions for anti-ferromagnetically coupled moieties, which will probably lead to heated discussions at conferences in the future.

Fully in silico design of enzymes is the holy grail of enzymology. The approaches that aim to create artificial metalloproteins exhibiting desired catalytic activity are now an emerging field of study, fuelled by progress made in deep learning strategies and the increase in computational power.² However, challenges persist, and natural enzymes still offer the best starting point as a basis that can be guided by mutations. The latter are often proposed by inspection of the crystal structure of a wild-type enzyme and tested experimentally. This is a tedious and not always effective process. Alternatively, theoretical methods can help uncover mutation-activity relationships more systematically. In this themed collection, de Visser and co-workers (https://doi.org/10.1039/D4CP01282H) decided to look at some selected cytochromes P450s (CYP) known to perform O-dealkylation or aromatic hydroxylation of some lignin-related molecules. Steering their reactivity towards specific products may enable the use of biodegraded natural materials – lignin – in more industrial processes. The authors provided a detailed analysis of wild-type enzyme activity via molecular dynamics (MD) and DFT studies. Furthermore, a set of mutations was investigated with MD, and the data were analysed using principal component analysis. One mutation was suggested to provide a stable protein with likely modified activity; subsequent DFT calculations showed that it alters the product preference from aromatic hydroxylation to O-dealkylation. Notably, MD alone would have suggested the opposite effect, highlighting the essential role of quantum-chemical methods in enzyme design.

We hope you enjoy reading the contents of this collection!

We acknowledge the following funding agencies: AK: National Science Centre of Poland, grant number 2020/39/B/ST4/01952. RB: French National Research Agency (Labex ARCANE). MS: Agencia Estatal de Investigación/Ministerio de Innovación, Ciencia y Universidades, Spain, PID2023-152415NB-I00 and Generalitat de Catalunya, Spain, 2021SGR00487.

References

1. I. Kipouros, H. Lim, M. J. Appel, K. K. Meier, B. Hedman, K. O. Hodgson, C. R. Bertozzi and E. I. Solomon, ACS Cent. Sci., 2025, 11(5), 683–693,  DOI:10.1021/acscentsci.5c00183.
2. S. L. Lovelock, R. Crawshaw, S. Basler, C. Levy, D. Baker, D. Hilvert and A. P. Green, Nature, 2022, 606, 49–58,  DOI:10.1038/s41586-022-04456-z.

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