Mintz Reshef, Raveh Barak
School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel.
Bioinform Adv. 2025 Jun 20;5(1):vbaf142. doi: 10.1093/bioadv/vbaf142. eCollection 2025.
Molecular dynamics (MD) simulations enable the study of complex biomolecular processes by integrating system forces over time, but their computational inefficiency limits application at relevant scales. Enhanced sampling methods often sacrifice kinetic detail and require prior knowledge of the energy landscape.
We developed the temporally multiscale prediction (TEMPO) Integrator, significantly reducing the number of force evaluations per simulated time unit by predicting forces at progressively larger intervals, thus boosting force-call efficiency. We incorporated the TEMPO integrator in a multiscale Brownian dynamics (MSBD) simulation tool. Compared with standard Brownian dynamics using the Euler-Maruyama integrator, our benchmarks of MSBD demonstrated 27- to 32-fold efficiency improvements for intrinsically disordered protein models and a seven-fold gain for nucleocytoplasmic transport through the nuclear pore complex (NPC), a critical cellular process in health and disease. Unlike conventional enhanced sampling, MSBD preserves kinetic properties, such as reaction rates, without relying on prior system knowledge or predefined reaction coordinates. By leveraging the inherently multiscale structure of energy landscapes, MSBD facilitates rapid molecular simulations while maintaining their accuracy. TEMPO's flexible framework is generalizable to various biomolecular systems and could complement existing enhanced sampling methods, facilitating efficient exploration of energy landscapes or complex dynamical processes.
分子动力学（MD）模拟通过对系统力随时间进行积分，能够研究复杂的生物分子过程，但其计算效率低下限制了在相关尺度上的应用。增强采样方法往往会牺牲动力学细节，并且需要能量景观的先验知识。
我们开发了时间多尺度预测（TEMPO）积分器，通过以逐渐增大的时间间隔预测力，显著减少了每个模拟时间单位的力评估次数，从而提高了力调用效率。我们将TEMPO积分器整合到一个多尺度布朗动力学（MSBD）模拟工具中。与使用欧拉 - 丸山积分器的标准布朗动力学相比，我们对MSBD的基准测试表明，对于内在无序蛋白质模型，效率提高了27至32倍，对于通过核孔复合体（NPC）的核质运输（这是健康和疾病中的一个关键细胞过程），效率提高了7倍。与传统的增强采样不同，MSBD保留了动力学性质，如反应速率，而无需依赖先验系统知识或预定义的反应坐标。通过利用能量景观固有的多尺度结构，MSBD在保持准确性的同时促进了快速分子模拟。TEMPO的灵活框架可推广到各种生物分子系统，并可补充现有的增强采样方法，便于对能量景观或复杂动力学过程进行高效探索。
