Importance of molecular dynamics equilibrium protocol on protein-lipid interaction near channel pore.
Importance of molecular dynamics equilibrium protocol on protein-lipid interaction near channel pore.
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DOI：
10.1016/j.bpr.2022.100080
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发表时间：
2022-12-14
期刊：
影响因子：
--
通讯作者：
Luo, Yun Lyna
中科院分区：
文献类型：
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作者：
Jiang, Wenjuan;Lacroix, Jerome;Luo, Yun Lyna
使用Martini粗粒（CG）和全原子（AA）力场的多尺度分子动力学模拟通常用于膜蛋白的研究。特别是，反向映射的平衡CG模型的AA模型提供了一种有效的方式来制备大的膜蛋白系统与复杂的蛋白质形状和脂质组成。在这里，我们报告说，这种混合CG-平衡AA-生产协议可能会人为地增加脂质密度和减少跨膜间隙壁的离子通道孔的水合作用。为了理解这个难题的起源，我们进行了复制品的CG，AA和CG反向映射AA模拟的孔域的机械敏感Piezo 1通道在非导电构象。脂质/水密度分析和自由能计算表明，初始孔隙水化的缺乏，允许过量的脂质进入上孔腔通过孔螺旋之间的间隙，在CG模拟。由于CG和AA脂质动力学之间的不匹配，这些孔脂质仍然被困在随后的AA模拟，尽管不利的结合自由能。我们测试了几种CG平衡方案，发现抑制整个脂质的方案产生与AA结果一致的孔水合作用，从而消除了这种人为因素，用于脂质门控和蛋白质-脂质相互作用的进一步研究。
Multiscale molecular dynamics simulations using Martini coarse-grained (CG) and all-atom (AA) force fields are commonly used in membrane protein studies. In particular, reverse mapping an equilibrated CG model to an AA model offers an efficient way for preparing large membrane protein systems with complex protein shapes and lipid compositions. Here, we report that this hybrid CG-equilibrium-AA-production protocol may artificially increase lipid density and decrease hydration in ion channel pores walled with transmembrane gaps. To understand the origin of this conundrum, we conducted replicas of CG, AA, and CG reverse-mapped AA simulations of the pore domain of the mechanosensitive Piezo1 channel in a nonconducting conformation. Lipid/water density analysis and free energy calculations reveal that the lack of initial pore hydration allows excessive lipids to enter the upper pore lumen through gaps between pore helices during CG simulation. Due to the mismatch between CG and AA lipid kinetics, these pore lipids remain trapped in the subsequent AA simulations, despite unfavorable binding free energy. We tested several CG equilibrium protocols and found that a protocol restraining the whole lipid produces pore hydration consistent with AA results, thus eliminating this artifact for further studies of lipid gating and protein-lipid interactions.