Multiscale Molecular Simulations in the Age of Exascale Computing.

Abstract

The interior of living cells is highly crowded with proteins, nucleic acids, and metabolites-a setting that simultaneously demands large system sizes and long simulation timescales. Exascale computing, now realized on modern supercomputers, offers a qualitatively new opportunity to address this challenge. In this review, we examine how multiscale molecular dynamics simulations-spanning all-atom, coarse-grained, and ultra-coarse-grained representations-are transforming our understanding of macromolecular crowding and liquid-liquid phase separation. We survey recent advances in force-field development, machine-learning-assisted system construction, and high-performance computing-optimized molecular dynamics engines, with particular attention to how these tools make large-scale simulations practically feasible. Key physical insights discussed include the interplay between excluded volume and nonspecific sticky interactions, crowding-induced slowdown of diffusion, metabolite-binding kinetics, and the regulatory mechanisms governing biomolecular condensate formation and maturation. We outline how exascale platforms, integrated with machine learning and experimental data, are bringing predictive whole-cell simulations within reach.

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