Carbonless Amino Acids and a Carbonless GHK Peptide

Abstract

Carbonless biomolecular design, in which carbon atoms are systematically replaced by boron and nitrogen under an isoelectronicity constraint, offers a route to carbon free analogues that retain the structural logic of familiar biochemistry. The concept is applied to amino acids and peptides, using glycine, histidine, lysine, and the tripeptide Gly–His–Lys (GHK) as a representative system. DFT(ωB97XD)/aug-cc-pVDZ calculations with aqueous PCM solvation, supported by CREST conformer sampling at the GFN2-xTB/ALPB level, identify unique low energy carbonless building blocks, cGly, cHis, and cLys, defined as carbonless analogues of Gly, His, and Lys among all isoelectronic BN constitutional isomers. These residues enable construction of cGHK, defined as the carbonless analogue of GHK, whose conformational landscape is predicted to be broader than that of GHK under physiological aqueous conditions, consistent with enhanced conformational plasticity. Cu(II) complexation is modeled with an experimentally supported 3N1O motif including one explicit water ligand, and an isodesmic ligand exchange thermodynamic cycle based on ensemble Gibbs free energies indicates stronger stabilization of Cu(II) by cGHK than by GHK (∆G_exch=−6.24 kcal/mol at 298 K), with only a minor ensemble correction. The results demonstrate the feasibility of carbonless amino acids and peptides and show that BN substitution can tune conformational behavior and metal binding thermodynamics in carbon free bioinspired scaffolds.