Folding-Driven Control of the Functional PP1 Complex via Multiscale Modeling

Abstract

Understanding how conformational dynamics regulate protein complex assembly remains a central challenge in molecular systems biology. Here, we develop a multiscale modeling framework that integrates all-atom molecular dynamics (MD) simulations with rule-based kinetic modeling to investigate formation of the PP1–GADD34–eIF2α complex, a critical regulator of the integrated stress response. Using umbrella sampling, we compute the potential of mean force (PMF) for key interactions, revealing strong thermodynamic driving forces for eIF2α binding (ΔG = –89.5 kJ/mol, KD ≈ 0.07 fM) and moderate affinity for PP1–GADD34 association (ΔG = –40.7 kJ/mol, KD ≈0.138 μM). These energetics inform a PySB-based model that incorporates GADD34’s folding state as a continuous variable (ϕ), linking conformational transitions to holoenzyme assembly and activity. Simulations show that catalytic efficiency is maximized when GADD34 folding free energy is 20 kJ/mol and ϕ = 0.9, reflecting a highly ordered state stabilized by actin and PP1 binding. Comparative analysis of energy-constrained and optimized parameter regimes reveals that folding-dependent assembly enhances both eIF2α dephosphorylation and information transmission, with channel capacities increasing from <0.002 bits to >5.5 bits. These results demonstrate how conformational regulation encodes system-level function and underscore the utility of multiscale models in bridging molecular energetics with dynamic biochemical control.