Computation-Guided Discovery of a Dual-Function Peptide from Rice Bran Hydrolysates: Nerve Agent VX Neutralization...

The highly lethal organophosphorus nerve agent S-{2-[di(propan-2-yl)amino]ethyl} O-ethyl methylphosphonothioate (VX) irreversibly inhibits acetylcholinesterase (AChE), necessitating advanced bioscavengers. Herein, peptide P15 (WEIKPSSLTGKSPYFSNNHGKL) identified from a natural hydrolysate database via Python-assisted filtering and hierarchical virtual screening was prioritized by MMPBSA binding free energy (ΔG_bind= -14.66 kcal/mol). Simulations reveal P15 neutralizes VX through a synergistic "scavenge-and-shield" mechanism. P15 directly sequesters free VX, while simultaneously inducing significant conformational and microenvironmental remodeling of the VX-AChE complex, selectively disrupting the electrostatic and hydrophobic networks requisite for VX accommodation. H-REMD/FEP calculations demonstrate this imposes a thermodynamic penalty (ΔΔG = +1.41 kcal/mol) on the VX-AChE complex. Steered molecular dynamics further showed P15 facilitates VX displacement, reducing the required rupture force by 53.3% (from 600 to 280 kJ/mol/nm). Supported by in vitro assays confirming P15's excellent biosafety (>100% cell viability), these computational findings indicate P15 integrates direct toxin scavenging with precise allosteric enzyme protection, serving as a promising dual-function countermeasure.