Shedding light on the HSAB-guided sulfur–selenium antagonism in mercury coordination and reactivity toward biologically relevant systems: a DFT and MD study

Abstract

The hard and soft acids and bases (HSAB) principle provides a foundational framework for predicting metal–ligand affinity. In biological systems, sulfur and selenium often display antagonistic behavior in binding metal ions such as Hg(II), owing to their similar chemical roles. This competition is critical both for understanding the toxic effects of Hg and also in the development of effective detoxification strategies. In this work, we present an in-depth computational study comparing mercury coordination to sulfur- and selenium-containing analogues of arginine vasopressin. These two cyclic nonapeptides serve as biologically relevant and structurally rich models for understanding soft metal–peptide interactions. Upon complexation with Hg(II), both peptides have the potential to form bridged S–Hg–S or Se–Hg–Se motifs, allowing a direct comparison of chalcogen-dependent coordination behavior under biologically realistic constraints. Using high-level density functional theory (DFT) and molecular dynamics (MD) simulations, we analyze structural, electronic, and mechanistic features governing Hg(II) complexation with sulfur- and selenium-based ligands. Our findings reveal that the Hg–S and Hg–Se complexes exhibit comparable coordination geometries, identical peptide folding characterized by similar hydrogen-bonding networks and binding energies. Bonding analyses suggest notable but not exceptional electronic differences: Se–Hg–Se bridges displayed stronger charge delocalization and higher covalency compared to their sulfur counterparts, reflecting selenium's greater polarizability. The most significant differences are found in the computed strain energies of these species, with Se complexes being considerably less strained than their sulfur analogues. Beyond structural effects, interaction with selenium exhibits a more distinct and far-reaching electronic influence, leading to deeper adjustment of the metal–ligand environment compared to sulfur. Furthermore, a detailed multistep reaction pathway analysis revealed lower activation barriers for Se–Hg–Se formation and a clear thermodynamic preference for the selenium-bridged species, also connected to the reduced strain energy penalties required for Hg(II) chelation. In line with the HSAB principle, these effects can be rationalized within the framework of conceptual DFT (CDFT) and condensed Fukui functions, which demonstrate selenium's higher local nucleophilicity/softness. MD simulations further demonstrate that selenium-containing ligands possess greater conformational flexibility, enabling more efficient metal coordination in aqueous environments. Overall, this study refines our understanding of HSAB predicted sulfur–selenium antagonism in peptide-based complex coordination environments and provides a theoretical foundation that could find prosperous ground in the design of more effective mercury chelation agents in biomedical and environmental contexts.