Conformational sampling of the botulinum neurotoxin serotype a light chain: implications for inhibitor binding

Molecular dynamics simulations were used to explore how residue motion in and around the botulinum neurotoxin serotype A light chain (BoNT/A LC) substrate binding cleft might affect inhibitor binding. Results from these studies indicate that surface loop reorientations toward the substrate binding cleft may facilitate small molecule binding by creating additional inhibitor-residue contacts. Based on molecular docking studies, our common pharmacophore model for BoNT/A LC inhibitors has been refined via the inclusion of these potential contact residues.