Carbonless amino acids and a carbonless GHK peptide.

This computational study introduces the concept of "carbonless" biomolecular design, in which all carbon atoms in amino acids and peptides are systematically replaced by boron and nitrogen atoms under an isoelectronicity constraint. Using glycine, histidine, lysine, and the copper-binding tripeptide Gly-His-Lys (GHK) as model systems, the researchers applied density functional theory (DFT) calculations with aqueous solvation modeling and conformer sampling to identify the most stable carbonless analogues (cGly, cHis, cLys, and cGHK) among all possible boron-nitrogen constitutional isomers. The study predicted that cGHK displays a broader conformational landscape than native GHK under physiological aqueous conditions, suggesting enhanced structural flexibility. Copper(II) binding was modeled using an experimentally informed coordination motif, and thermodynamic calculations indicated that cGHK binds Cu(II) more favorably than GHK by approximately 6.24 kcal/mol. The work is entirely theoretical; no synthesis, cell-based, animal, or human experiments were conducted. Limitations include the absence of experimental validation of the proposed carbonless structures, reliance on computational approximations for solvation and conformational sampling, and uncertainty about whether these novel BN-substituted molecules could be synthesized or would exhibit biological stability.

Why this grade: The study is entirely computational (DFT and semi-empirical modeling) with no experimental, animal, or human data, providing no direct evidence of biological activity or efficacy in any living system.