Truong Ha H, Kim Bobby L, Schafer Nicholas P, Wolynes Peter G
Department of Chemistry, Rice University, Houston, Texas 77005, USA.
Center for Theoretical Biological Physics, Rice University, Houston, Texas 77005, USA.
J Chem Phys. 2015 Dec 28;143(24):243101. doi: 10.1063/1.4929598.
We study the energy landscapes for membrane protein oligomerization using the Associative memory, Water mediated, Structure and Energy Model with an implicit membrane potential (AWSEM-membrane), a coarse-grained molecular dynamics model previously optimized under the assumption that the energy landscapes for folding α-helical membrane protein monomers are funneled once their native topology within the membrane is established. In this study we show that the AWSEM-membrane force field is able to sample near native binding interfaces of several oligomeric systems. By predicting candidate structures using simulated annealing, we further show that degeneracies in predicting structures of membrane protein monomers are generally resolved in the folding of the higher order assemblies as is the case in the assemblies of both nicotinic acetylcholine receptor and V-type Na(+)-ATPase dimers. The physics of the phenomenon resembles domain swapping, which is consistent with the landscape following the principle of minimal frustration. We revisit also the classic Khorana study of the reconstitution of bacteriorhodopsin from its fragments, which is the close analogue of the early Anfinsen experiment on globular proteins. Here, we show the retinal cofactor likely plays a major role in selecting the final functional assembly.
我们使用具有隐式膜电位的关联记忆、水介导、结构和能量模型（AWSEM-膜）来研究膜蛋白寡聚化的能量景观，这是一种粗粒度分子动力学模型，之前在假设α-螺旋膜蛋白单体在膜内建立其天然拓扑结构后折叠的能量景观呈漏斗状的前提下进行了优化。在本研究中，我们表明AWSEM-膜力场能够对几个寡聚系统的近天然结合界面进行采样。通过使用模拟退火预测候选结构，我们进一步表明，在预测膜蛋白单体结构时的简并性在高阶组装体折叠过程中通常会得到解决，烟碱型乙酰胆碱受体和V型Na(+)-ATP酶二聚体的组装情况就是如此。该现象的物理原理类似于结构域交换，这与遵循最小受挫原则的能量景观一致。我们还重新审视了经典的霍拉纳（Khorana）关于从细菌视紫红质片段重建细菌视紫红质的研究，这类似于早期安芬森（Anfinsen）对球状蛋白的实验。在这里，我们表明视网膜辅因子可能在选择最终功能组装体中起主要作用。
