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。 跨膜结构域与脂双层之间的疏水匹配已被认为是蛋白质-脂相互作用和膜蛋白功能双层调控的核心特征。传统上，人们设想跨膜螺旋可以倾斜或扭结，以克服疏水错配引起的不利相互作用。为了确定控制膜螺旋倾斜的微观作用力，我们最近计算了跨膜模型多肽WALP19在DMPC膜中的平均作用力势随倾斜角的变化。平均力的总势及其分解表明，膜中的螺旋倾斜是由围绕膜法线的螺旋进动产生的内禀熵贡献与特定序列和长度的螺旋-脂质相互作用之间的相互作用所决定的。基于这一关于膜螺旋倾斜的新观点，我们建议扩展平均力势的计算，以丰富我们对疏水失配对跨膜螺旋倾斜影响的理解。特定的螺旋-脂质相互作用在螺旋倾斜中的作用将通过对不同疏水长度的跨膜螺旋、不同膜界面的不同锚定残基和不同疏水厚度的脂双层进行平均力计算来确定。

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. The hydrophobic match between transmembrane domains and the lipid bilayer has been recognized as a central feature in protein-lipid interactions and bilayer regulation of membrane protein functions. Traditionally, people have envisioned that a transmembrane helix may tilt or kink in order to overcome unfavorable interactions arising from a hydrophobic mismatch. To determine the microscopic forces governing the helix tilting in membranes, we have recently calculated the potential of mean force as a function of tilt angle of WALP19, a transmembrane model peptide, in a DMPC membrane. The total potential of mean force and its decomposition reveal that the helix tilting in membranes is governed by interplay between an intrinsic entropy contribution arising from the helix precession around the membrane normal and the sequence- and length-specific helix-lipid interactions. Based on this novel view on helix tilting in membranes, we propose to extend the calculations of potentials of mean force to enrich our understanding of the influence of a hydrophobic mismatch on transmembrane helix tilting. The role of specific helix-lipid interactions in the helix tilting will be determined by performing potential of mean force calculations with transmembrane helices with different hydrophobic lengths, different anchoring residues at the membrane interface, and lipid bilayers with different hydrophobic thicknesses.