UNDERSTANDING OF HYDROPHOBIC MISMATCH BY POTENTIALS OF MEAN FORCE CALCULATIONS

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 膜蛋白或跨膜（TM）螺旋肽可以倾斜或扭结以克服由TM结构域的疏水长度与膜双层的疏水长度之间的错配产生的不利相互作用，这概括为“疏水错配”概念。最近，已经使用固态NMR测量了具有不同长度的疏水核的各种双层中HIV-1的Vpu TM结构域的倾斜角。随着膜的疏水核的厚度减小，倾斜角急剧增加。本研究的目的是通过计算平均力（PMFs）的电位作为嵌入在显式膜中的Vpu TM域的倾斜角的函数来确定这种变化的微观起源。螺旋倾斜角相对于膜法线被限制在特定值附近波动，使用倾斜角约束电位，我们最近开发的。在模拟中使用的显式膜是POPC、DMPC、12：0-O-PC和10：0-O-PC，其在实验中用于模拟不同长度的膜疏水核。这项研究是有意义的，因为它将提供详细的信息，潜在的微观力量，管理的反应螺旋TM肽的疏水性错配。这些信息可用于进一步开发和改进作为药学上重要的治疗靶点的膜蛋白的建模工具。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Membrane proteins or transmembrane (TM) helical peptides may tilt or kink in order to overcome unfavorable interactions that arise from mismatch between the hydrophobic length of TM domains and that of membrane bilayer, which is recapitulated as the "hydrophobic mismatch" concept. Recently, the tilt angles of Vpu TM domain from HIV-1 have been measured in various bilayers with different lengths of hydrophobic core using solid-state NMR. The tilt angle increases dramatically as the thickness of the hydrophobic core of membranes decreases. The goal of this research proposal is to determine the microscopic origins of such a change by calculating the potentials of mean force (PMFs) as a function of tilt angle of Vpu TM domain embedded in explicit membranes. The helical tilt angles relative to membrane normal are restrained to fluctuate around the specific values using the tilt angle restraint potential that we have recently developed. The explicit membranes used in the simulations are POPC, DMPC, 12:0-O-PC, and 10:0-O-PC that were used in the experiments to model different lengths of membrane hydrophobic core. This research is significant because it will provide the detailed information on underlying microscopic forces that govern the responses of helical TM peptides to the hydrophobic mismatch. Such information can be used to further develop and improve modeling tools of membrane proteins that are pharmaceutically important therapeutic targets.