UNDERSTANDING OF HYDROPHOBIC MISMATCH BY POTENTIALS OF MEAN FORCE CALCULATIONS

这个子项目是许多研究子项目中的一个 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来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 跨膜结构域和脂质双层之间的疏水匹配已被认为是蛋白质-脂质相互作用和膜蛋白功能的双层调节的中心特征。传统上，人们设想跨膜螺旋可以倾斜或扭结，以克服由疏水性错配引起的不利相互作用。为了确定在膜中的螺旋倾斜的微观力，我们最近计算了作为跨膜模型肽WALP 19在DMPC膜中的倾斜角的函数的平均力的潜力。平均力和它的分解的总潜力表明，在膜中的螺旋倾斜是由一个内在的熵的贡献所产生的螺旋旋进周围的膜正常和序列和长度特定的螺旋-脂质相互作用之间的相互作用。基于这种新的观点在膜中的螺旋倾斜，我们建议扩展计算的平均力的潜力，以丰富我们的理解的疏水性错配跨膜螺旋倾斜的影响。特定螺旋-脂质相互作用在螺旋倾斜中的作用将通过使用具有不同疏水长度的跨膜螺旋、膜界面处的不同锚定残基和具有不同疏水厚度的脂质双层进行平均力计算的潜力来确定。

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.