Free energy, rates, and mechanism of transmembrane dimerization in lipid bilayers from dynamically unbiased molecular dynamics simulations

Emil Jackel, Gianmarco Lazzeri, Roberto Covino
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Abstract

The assembly of proteins in membranes plays a key role in many crucial cellular pathways. Despite their importance, characterizing transmembrane assembly remains challenging for experiments and simulations. Equilibrium molecular dynamics simulations do not cover the time scales required to sample the typical transmembrane assembly. Hence, most studies rely on enhanced sampling schemes that steer the dynamics of transmembrane proteins along a collective variable that should encode all slow degrees of freedom. However, given the complexity of the condensed-phase lipid environment, this is far from trivial, with the consequence that free energy profiles of dimerization can be poorly converged. Here, we introduce an alternative approach, which relies only on simulating short, dynamically unbiased trajectory segments, avoiding using collective variables or biasing forces. By merging all trajectories, we obtain free energy profiles, rates, and mechanisms of transmembrane dimerization with the same set of simulations. We showcase our algorithm by sampling the spontaneous association and dissociation of a transmembrane protein in a lipid bilayer, the popular coarse-grained Martini force field. Our algorithm represents a promising way to investigate assembly processes in biologically relevant membranes, overcoming some of the challenges of conventional methods.
从动态无偏分子动力学模拟看脂质双层膜中跨膜二聚化的自由能、速率和机理
蛋白质在膜中的组装在许多重要的细胞通路中起着关键作用。尽管跨膜组装非常重要,但表征跨膜组装对于实验和模拟来说仍然具有挑战性。平衡分子动力学模拟无法覆盖典型跨膜组装取样所需的时间尺度。因此,大多数研究都依赖于增强的取样方案,这种方案会引导跨膜蛋白的动力学沿着一个应编码所有慢自由度的集合变量进行。然而,考虑到凝聚相脂质环境的复杂性,这绝非易事,其结果是二聚化的自由能曲线收敛性很差。在这里,我们引入了另一种方法,即只模拟短的、动态无偏的轨迹片段,避免使用集合变量或偏向力。通过合并所有轨迹,我们在同一组模拟中获得了跨膜二聚化的自由能谱、速率和机制。我们通过采样脂质层中跨膜蛋白的自发结合和解离,展示了我们的算法。我们的算法为研究生物相关膜的组装过程提供了一种很有前景的方法,克服了传统方法所面临的一些挑战。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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