论文标题
评估过渡速率作为环境变量的功能
Assessing transition rates as functions of environmental variables
论文作者
论文摘要
我们提出了一种在不同的环境条件下估算分子系统过渡速率的方法，这些环境条件会导致形成或断裂键，并需要对大规范合奏的采样。为此，我们根据可能的“场景”对分子系统进行建模，并由不同的势能函数控制，这些势能函数由经典MD模拟分别对其进行了采样。根据特定的环境变量将每种情况的典范分布重新权予以估计，我们估计了大规范分布，然后我们使用平方根近似（SQRA）方法将fokker-Planck运算符离散为速率矩阵中，并将其分散到速率矩阵中，并将其稳定的Perron群集群集群集分析（PCCA+）方法分散到kinetic群集分析（PCCA+）方法。这允许有效估计构象状态的过渡速率，例如环境变量的功能，例如在细胞膜处的局部pH。在这项工作中，我们将过程的理论框架形式化，并提出了一个数值实验，将结果与基于非平衡分子动力学蒙特卡洛模拟的恒定PH方法提供的结果进行了比较。该方法与开发新药物设计策略有关，该策略考虑了细胞环境如何影响生化过程。
We present a method to estimate the transition rates of molecular systems under different environmental conditions which cause the formation or the breaking of bonds and require the sampling of the Grand Canonical Ensemble. For this purpose, we model the molecular system in terms of probable "scenarios", governed by different potential energy functions, which are separately sampled by classical MD simulations. Reweighting the canonical distribution of each scenario according to specific environmental variables, we estimate the grand canonical distribution, then we use the Square Root Approximation (SqRA) method to discretize the Fokker-Planck operator into a rate matrix and the robust Perron Cluster Cluster Analysis (PCCA+) method to coarse-grain the kinetic model. This permits to efficiently estimate the transition rates of conformational states as functions of environmental variables, for example, the local pH at a cell membrane. In this work we formalize the theoretical framework of the procedure and we present a numerical experiment comparing the results with those provided by a constant-pH method based on non-equilibrium Molecular Dynamics Monte Carlo simulations. The method is relevant for the development of new drug design strategies which take into account how the cellular environment influences biochemical processes.
