Departamento de Química Fundamental, Universidade Federal de Pernambuco, Cidade Universitária, 50670-901 Recife, Brazil.
Molecules. 2020 Nov 4;25(21):5120. doi: 10.3390/molecules25215120.
Molecular dynamics (MD) simulations represent an essential tool in the toolbox of modern chemistry, enabling the prediction of experimental observables for a variety of chemical systems and processes and majorly impacting the study of biological membranes. However, the chemical diversity of complex lipids beyond phospholipids brings new challenges to well-established protocols used in MD simulations of soft matter and requires continuous assessment to ensure simulation reproducibility and minimize unphysical behavior. Lipopolysaccharides (LPS) are highly charged glycolipids whose aggregation in a lamellar arrangement requires the binding of numerous cations to oppositely charged groups deep inside the membrane. The delicate balance between the fully hydrated carbohydrate region and the smaller hydrophobic core makes LPS membranes very sensitive to the choice of equilibration protocol. In this work, we show that the protocol successfully used to equilibrate phospholipid bilayers when applied to complex lipopolysaccharide membranes occasionally leads to a small expansion of the simulation box very early in the equilibration phase. Although the use of a barostat algorithm controls the system dimension and particle distances according to the target pressure, fluctuation in the fleeting pressure occasionally enables a few water molecules to trickle into the hydrophobic region of the membrane, with spurious solvent buildup. We show that this effect stems from the initial steps of NPT equilibration, where initial pressure can be fairly high. This can be solved with the use of a stepwise-thermalization NVT/NPT protocol, as demonstrated for atomistic MD simulations of LPS/DPPE and lipid-A membranes in the presence of different salts using an extension of the GROMOS forcefield within the GROMACS software. This equilibration protocol should be standard procedure for the generation of consistent structural ensembles of charged glycolipids starting from atomic coordinates not previously pre-equilibrated. Although different ways to deal with this issue can be envisioned, we investigated one alternative that could be readily available in major MD engines with general users in mind.
分子动力学（MD）模拟是现代化学工具箱中的重要工具，能够预测各种化学系统和过程的实验可观测结果，对生物膜的研究产生了重大影响。然而，磷脂以外的复杂脂质的化学多样性给软物质 MD 模拟中使用的成熟协议带来了新的挑战，需要不断评估以确保模拟的可重复性并最小化非物理行为。脂多糖（LPS）是高度带电的糖脂，其在层状排列中的聚集需要将大量阳离子结合到膜内带相反电荷的基团上。完全水合的碳水化合物区域和较小的疏水区之间的微妙平衡使得 LPS 膜对平衡协议的选择非常敏感。在这项工作中，我们表明，当应用于复杂的脂多糖膜时，成功用于平衡磷脂双层的协议偶尔会在平衡阶段的早期导致模拟盒的轻微膨胀。尽管使用压力计算法根据目标压力控制系统维度和粒子距离，但压力的波动偶尔会使几个水分子涌入膜的疏水区，从而产生虚假的溶剂堆积。我们表明，这种效应源于 NPT 平衡的初始步骤，其中初始压力可能相当高。可以使用逐步热化 NVT/NPT 协议来解决此问题，如使用 GROMACS 软件中 GROMOS 力场的扩展，针对 LPS/DPPE 和脂质-A 膜在不同盐存在下的原子 MD 模拟所示。对于从原子坐标开始生成未预先平衡的带电糖脂一致的结构集合，此平衡协议应成为标准程序。虽然可以设想处理此问题的不同方法，但我们研究了一种替代方法，该方法可以在主要的 MD 引擎中为一般用户提供。
