Exploring the noncovalent chemistry in the catalytic centers of Snake Venom Metalloproteinases: A computational perspective

Abstract

Snakebite envenoming is a major neglected tropical disease, in which snake venom metalloproteinases (SVMPs) are key drivers of local tissue damage, microvascular disruption, and hemostatic imbalance. Closely related SVMPs can nevertheless range from highly hemorrhagic to essentially non-hemorrhagic while sharing a conserved Zn(II) catalytic site, and the structural causes of this divergence (particularly the role of the conserved methionine-containing turn (MET-turn) beneath the metal center) remain unclear. Here, we have combined a Protein Data Bank (PDB) inspection with theoretical calculations at the PBE0-D3/def2-TZVP level to investigate the noncovalent interactions stabilizing the MET residue over the Zn(II) catalytic site in both hemorrhagic and non-hemorrhagic P-I and P-III SVMPs. Additionally, the results were analyzed using several computational tools, such as the Quantum Theory of Atoms in Molecules (QTAIM) and the Non Covalent Interaction plot (NCIplot) methodologies, revealing and quantifying S lone pair–π, CH–π and Zn-associated σ-hole (Spodium bond-like) interactions. We believe the results presented herein will be useful to those scientists devoted to bioinorganic chemistry and rational drug design as well as to expand the current knowledge of SpBs among the chemical biology community.