Laboratory of Computational Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
IBiTech - BioMMeda, Ghent University, Corneel Heymanslaan 10, Block B - Entrance 36, 9000 Gent, Belgium.
J Chem Phys. 2020 Sep 28;153(12):124107. doi: 10.1063/5.0013429.
Permeation of many small molecules through lipid bilayers can be directly observed in molecular dynamics simulations on the nano- and microsecond timescale. While unbiased simulations provide an unobstructed view of the permeation process, their feasibility for computing permeability coefficients depends on various factors that differ for each permeant. The present work studies three small molecules for which unbiased simulations of permeation are feasible within less than a microsecond, one hydrophobic (oxygen), one hydrophilic (water), and one amphiphilic (ethanol). Permeabilities are computed using two approaches: counting methods and a maximum-likelihood estimation for the inhomogeneous solubility diffusion (ISD) model. Counting methods yield nearly model-free estimates of the permeability for all three permeants. While the ISD-based approach is reasonable for oxygen, it lacks precision for water due to insufficient sampling and results in misleading estimates for ethanol due to invalid model assumptions. It is also demonstrated that simulations using a Langevin thermostat with collision frequencies of 1/ps and 5/ps yield oxygen permeabilities and diffusion constants that are lower than those using Nosé-Hoover by statistically significant margins. In contrast, permeabilities from trajectories generated with Nosé-Hoover and the microcanonical ensemble do not show statistically significant differences. As molecular simulations become more affordable and accurate, calculation of permeability for an expanding range of molecules will be feasible using unbiased simulations. The present work summarizes theoretical underpinnings, identifies pitfalls, and develops best practices for such simulations.
许多小分子通过脂质双层的渗透可以在纳秒和微秒时间尺度上的分子动力学模拟中直接观察到。虽然无偏模拟提供了渗透过程的无障碍视图，但它们计算渗透率的可行性取决于各种因素，这些因素因每种渗透物而异。本工作研究了三种小分子，对于这三种小分子，无偏模拟渗透在不到 1 微秒的时间内是可行的，一种疏水性（氧），一种亲水性（水）和一种两亲性（乙醇）。渗透率使用两种方法计算：计数方法和非均相溶解度扩散（ISD）模型的最大似然估计。计数方法为所有三种渗透物提供了几乎无模型的渗透率估计。虽然基于 ISD 的方法对于氧是合理的，但由于采样不足，对于水的精度不够，并且由于模型假设无效，对于乙醇会导致误导性估计。还证明，使用碰撞频率为 1/ps 和 5/ps 的 Langevin 恒温器进行模拟会导致氧渗透率和扩散常数低于使用 Nosé-Hoover 的情况，这具有统计学意义。相比之下，使用 Nosé-Hoover 和微正则系综生成的轨迹的渗透率没有表现出统计学上的显著差异。随着分子模拟变得更加经济实惠和准确，使用无偏模拟计算越来越多分子的渗透率将成为可行的。本工作总结了理论基础，确定了陷阱，并为这种模拟制定了最佳实践。
