UNDERSTANDING OF HYDROPHOBIC MISMATCH BY POTENTIALS OF MEAN FORCE CALCULATIONS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 膜蛋白或跨膜(TM)螺旋肽可以倾斜或扭结，以克服TM结构域的疏水长度与膜双层的疏水长度之间的不匹配引起的不利相互作用，这被概括为“疏水不匹配”概念。最近，用固体核磁共振技术测量了HIV-1在不同长度疏水核心层中的VPU TM结构域的倾斜角。随着膜疏水芯层厚度的减小，膜的倾斜角急剧增大。这项研究的目标是通过计算平均力势(PMF)作为嵌入在显性膜中的VPU TM结构域倾斜角的函数来确定这种变化的微观起源。利用我们最近开发的倾斜角限制势，相对于膜法线的螺旋倾斜角被限制在特定值附近波动。模拟中使用的显式膜是POPC、DMPC、12：0-O-PC和10：0-O-PC，它们被用于模拟不同长度的膜疏水核心。这项研究具有重要意义，因为它将提供关于控制螺旋TM多肽对疏水错配反应的潜在微观作用力的详细信息。这些信息可用于进一步开发和改进膜蛋白的建模工具，膜蛋白是重要的药物治疗靶点。

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.