A Multi-Scale Computational Analysis of Bucillamine Neuroprotection Against Soman Toxicity

This computational framework evaluates the neuroprotective mechanism of the dithiol antioxidant Bucillamine (and its active metabolite SA981) against Soman-induced oxidative damage. By integrating quantum chemical calculations, classical molecular dynamics, and systems-level ordinary differential equation (ODE) modeling, this work establishes a multi-scale predictive chain that identifies catalytic longevity as a key metric for antioxidant efficacy under acute nerve-agent stress.

Key Methodological Layers:

• Transport Energetics: Human LAT1 (PDB 7DSQ) and xCT (PDB 7P9U) transport barriers are computed using 3,660 ns of umbrella sampling PMF simulations.

• QM/MM Disulfide-Exchange Energetics: The reaction coordinate for Somatostatin (SST) disulfide cleavage is modeled using gas-phase Density Functional Theory (DFT) relaxed scans at the PBE-D3/DZVP level of theory.

• Systems Pharmacology Modeling: A 28-variable ODE model of Soman neurotoxicity and antioxidant kinetics is constructed and calibrated to empirical literature targets using Bayesian Markov Chain Monte Carlo (MCMC) parameter estimation with the emcee ensemble sampler.

• Global Sensitivity & Counterfactual Analysis: Global sensitivity analysis via Sobol variance decomposition ($N = 22,528$ model evaluations) isolates the primary drivers of ROS variance. Computational counterfactuals are used to systematically disable individual pathway modules to map the causal hierarchy of neuroprotection.

Core Scientific Findings:

• The Catalytic Longevity Paradigm: Due to its dithiol structure, a single Bucillamine molecule can undergo an estimated 500 to 5,000 ROS-scavenging cycles under severe stress before irreversible overoxidation, compared to only ~11 cycles for single-thiol counterparts like cysteamine.

• The Reduced-Species Route: Direct exchange between intact cyclic disulfides is highly barrier-limited (barrier $\ge$ 40 kcal/mol). In contrast, the reduced Bucillamine thiolate presents a dramatically lower barrier (~2.5 kcal/mol), demonstrating that intracellular reduction is a strict mechanistic prerequisite for downstream somatostatin depletion.

• The Therapeutic Window: Calibrated GSH-dependent dynamics predict that the catalytic cycle maintains high efficacy for 4 to 5 hours before GSH depletion terminates the cycle, validating the clinical potential of delayed antioxidant intervention up to 240 minutes post-exposure.