Highly Optimized Simulation of Atomic Resolution Cell-Like Protein Environment.

Computational approaches can provide details of molecular mechanisms in a crowded environment inside cells. Protein docking predicts stable configurations of molecular complexes, which correspond to deep energy minima. Systematic docking approaches, such as those based on fast Fourier transform (FFT), also map the entire intermolecular energy landscape by determining the position and depth of the full spectrum of the energy minima. Such mapping allows speeding up simulations by precalculating the intermolecular energy values. Our earlier study combined FFT docking with the Monte Carlo protocol, enabling simulation of cell-size, crowded protein systems with seconds, and longer trajectories at atomic resolution, several orders of magnitude longer than those achievable by alternative approaches. In this study, we present a further drastic extension of the modeling capabilities by parallelized implementation of the simulation protocol. The procedure was applied to a panel of Death Fold Domains that form nucleated polymers in human innate immune signaling, recapitulating their homooligomerization tendencies and providing insights into the molecular mechanisms of polymer nucleation. The parallelized protocol allows extension of the simulation trajectories by orders of magnitude beyond the previously reported implementation, reaching into the uncharted territory of atomic resolution simulation of cell-sized systems.