Groningen Biomolecular Sciences and Biotechnology Institute & Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands.
J Phys Chem B. 2013 Apr 4;117(13):3516-30. doi: 10.1021/jp311533p. Epub 2013 Mar 6.
Hybrid molecular dynamics simulations of atomistic (AA) solutes embedded in coarse-grained (CG) environment can substantially reduce the computational cost with respect to fully atomistic simulations. However, interfacing both levels of resolution is a major challenge that includes a balanced description of the relevant interactions. This is especially the case for polar solvents such as water, which screen the electrostatic interactions and thus require explicit electrostatic coupling between AA and CG subsystems. Here, we present and critically test computationally efficient hybrid AA/CG models. We combined the Gromos atomistic force field with the MARTINI coarse-grained force field. To enact electrostatic coupling, two recently developed CG water models with explicit electrostatic interactions were used: the polarizable MARTINI water model and the BMW model. The hybrid model was found to be sensitive to the strength of the AA-CG electrostatic coupling, which was adjusted through the relative dielectric permittivity εr(AA-CG). Potentials of mean force (PMFs) between pairs of amino acid side chain analogues in water and partitioning free enthalpies of uncharged amino acid side chain analogues between apolar solvent and water show significant differences between the hybrid simulations and the fully AA or CG simulations, in particular for charged and polar molecules. For apolar molecules, the results obtained with the hybrid AA/CG models are in better agreement with the fully atomistic results. The structures of atomistic ubiquitin solvated in CG water and of a single atomistic transmembrane α-helix and the transmembrane portion of an atomistic mechanosensitive channel in CG lipid bilayers were largely maintained during 50-100 ns of AA/CG simulations, partly due to an overstabilization of intramolecular interactions. This work highlights some key challenges on the way toward hybrid AA/CG models that are both computationally efficient and sufficiently accurate for biomolecular simulations.
杂化分子动力学模拟可以将原子（AA）溶质嵌入粗粒（CG）环境中，相对于完全原子模拟，可以大大降低计算成本。然而，界面两个分辨率水平是一个主要的挑战，包括对相关相互作用的平衡描述。对于像水这样的极性溶剂来说，情况更是如此，因为水会屏蔽静电相互作用，因此需要在 AA 和 CG 子系统之间进行明确的静电耦合。在这里，我们提出并严格测试了计算效率高的杂化 AA/CG 模型。我们将 Gromos 原子力场与 MARTINI 粗粒力场相结合。为了实现静电耦合，使用了两种最近开发的具有显式静电相互作用的 CG 水模型：可极化的 MARTINI 水模型和 BMW 模型。混合模型对 AA-CG 静电耦合的强度很敏感，通过相对介电常数 εr(AA-CG)来调整。在水中成对氨基酸侧链类似物之间的平均力势（PMF）和不带电荷的氨基酸侧链类似物在非极性溶剂和水中的分配自由焓之间的差异表明，混合模拟与完全 AA 或 CG 模拟之间存在显著差异，特别是对于带电和极性分子。对于非极性分子，混合 AA/CG 模型得到的结果与完全原子的结果更为一致。在 50-100ns 的 AA/CG 模拟中，原子化泛素在 CG 水中的溶剂化结构以及单个原子化跨膜α-螺旋和原子化机械敏感通道的跨膜部分的结构在很大程度上得以维持，部分原因是分子内相互作用的过度稳定。这项工作突出了杂化 AA/CG 模型在计算效率和对生物分子模拟的准确性方面所面临的一些关键挑战。
