分子潜在空间模拟器

Molecular latent space simulators.

作者信息

Sidky Hythem, Chen Wei, Ferguson Andrew L

机构信息

Pritzker School of Molecular Engineering, University of Chicago Chicago USA

Department of Physics, University of Illinois at Urbana-Champaign Urbana USA.

出版信息

Chem Sci. 2020 Aug 26;11(35):9459-9467. doi: 10.1039/d0sc03635h.

Abstract

Small integration time steps limit molecular dynamics (MD) simulations to millisecond time scales. Markov state models (MSMs) and equation-free approaches learn low-dimensional kinetic models from MD simulation data by performing configurational or dynamical coarse-graining of the state space. The learned kinetic models enable the efficient generation of dynamical trajectories over vastly longer time scales than are accessible by MD, but the discretization of configurational space and/or absence of a means to reconstruct molecular configurations precludes the generation of continuous atomistic molecular trajectories. We propose latent space simulators (LSS) to learn kinetic models for continuous atomistic simulation trajectories by training three deep learning networks to (i) learn the slow collective variables of the molecular system, (ii) propagate the system dynamics within this slow latent space, and (iii) generatively reconstruct molecular configurations. We demonstrate the approach in an application to Trp-cage miniprotein to produce novel ultra-long synthetic folding trajectories that accurately reproduce atomistic molecular structure, thermodynamics, and kinetics at six orders of magnitude lower cost than MD. The dramatically lower cost of trajectory generation enables greatly improved sampling and greatly reduced statistical uncertainties in estimated thermodynamic averages and kinetic rates.

摘要

小的积分时间步长将分子动力学(MD)模拟限制在毫秒时间尺度。马尔可夫状态模型(MSMs)和无方程方法通过对状态空间进行构型或动力学粗粒化,从MD模拟数据中学习低维动力学模型。所学习的动力学模型能够在比MD可及的时间尺度长得多的时间尺度上高效生成动力学轨迹,但构型空间的离散化和/或缺乏重建分子构型的方法,排除了生成连续原子分子轨迹的可能性。我们提出潜在空间模拟器(LSS),通过训练三个深度学习网络来学习连续原子模拟轨迹的动力学模型,这三个网络分别用于(i)学习分子系统的慢集体变量,(ii)在这个慢潜在空间内传播系统动力学,以及(iii)生成性地重建分子构型。我们在色氨酸笼状小蛋白的应用中展示了该方法,以产生新颖的超长合成折叠轨迹,其能以比MD低六个数量级的成本准确再现原子分子结构、热力学和动力学。轨迹生成成本的大幅降低使得采样得到极大改善,并且估计的热力学平均值和动力学速率的统计不确定性大大降低。

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