Simulation of lipid-protein interactions with the CgProt force field
Simulation of lipid-protein interactions with the CgProt force field
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DOI：
10.3934/molsci.2017.3.352
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发表时间：
2017-01-01
影响因子：
1.4
通讯作者：
Hills, Ronald D., Jr.
中科院分区：
文献类型：
--
作者：
Fosso-Tande, Jacob;Black, Cody;Hills, Ronald D., Jr.
脂质-蛋白质相互作用对膜蛋白及其功能的影响正在成为生物物理学的一个重要领域。最近开发的 CgProt 力场用于通过脂双层环境下的粗粒度分子动力学模拟来探索肽和蛋白质的分子水平相互作用。检查了设计的螺旋肽 WALP27：GWW(LA)ioLWWA 和 LS3：(LSSLLSL)3 的膜插入机制。 WALP27 采用跨膜构象，而 LS3 在不同起始条件的独立模拟中采用界面和跨膜取向。在 LS3 和 WALP 的无偏分子动力学模拟中总共观察到 13 个肽插入事件。每个案例均通过带电的 N 末端穿过双层进行。在平衡构象中，C 末端位于 DOPC 双层的头基区域，而 N 末端则深入羰基区域。这些发现与最近关于正电荷对膜界面的吸引力的证据是一致的。通过模拟 12 次跨膜螺旋多药物转运蛋白 P-糖蛋白，探索了膜蛋白天然环境中脂质相互作用的作用。对含有 20% 胆固醇的 POPC:POPE 双层中的脂质密度进行分析，发现磷脂酰胆碱和胆固醇的环形溶剂化壳与膜中的蛋白质一起扩散。 P-糖蛋白的内向状态经历了向闭合状态的构象转变，证实了最近通过同源建模和分子动力学模拟生成的 ATP 结合状态的结构模型。
The effect of lipid-protein interactions on membrane proteins and their function is emerging as an important area in biophysics. The recently developed CgProt force field is used to explore molecular level interactions in peptides and proteins through coarse-grained molecular dynamics simulations in the presence of the lipid bilayer environment. The mechanism of membrane insertion was examined for designed helical peptides WALP27: GWW(LA)ioLWWA and LS3: (LSSLLSL)3. WALP27 adopts a transmembrane conformation while LS3 adopts interfacial and transmembrane orientations in independent simulations from different starting conditions. A total of 13 peptide insertion events were observed in unbiased molecular dynamics simulations of LS3 and WALP. Each case proceeded via the charged N-terminus crossing the bilayer. In the equilibrated conformations, the C-terminus resides in the head group region of the DOPC bilayer, while the N-terminus submerges deep into the carbonyl region. These findings are consistent with recent evidence of the attractive nature of positive charges for the membrane interface. The role of lipid interactions in the native environment of a membrane protein was explored by simulation of a 12-transmembrane helix multidrug transporter, P-glycoprotein. Analysis of the lipid density in a POPC: POPE bilayer containing 20% cholesterol revealed an annular solvation shell of phosphatidyl choline and cholesterol that diffuses with the protein in the membrane. The inward-facing state of P-glycoprotein undergoes a conformational transition to the closed state, corroborating a structural model for the ATP-bound state recently generated by homology modeling and molecular dynamics simulation.