Computational Studies of Helix and Beta-Hairpin Dynamics and Orientation in Biological Membranes

尽管在实验和计算方法上都取得了相当大的进展来研究生物重要的膜蛋白，但确定它们在生物膜中的结构和动力学仍然具有挑战性。该项目旨在通过计算平均力（PMF）的潜力沿着其方向和通过执行系综动力学与可用的取向NMR观测来表征膜环境中的螺旋/β-发夹的动力学和取向。这项研究将为以下重要的生物物理问题提供新的见解。为什么单个跨膜螺旋或β-发夹在膜中具有特定的方向？氢键、紧密堆积和β-发夹-脂质相互作用在膜中β-发夹缔合中的作用是什么？什么是动态信息嵌入在核磁共振数据获得对齐的样品或什么是影响螺旋动力学对这样的可观的？PMF的计算和它们分解成各种微观贡献将丰富我们的理解跨膜螺旋/β-发夹方向和相互作用的分子基础，通过确定微妙的平衡力的螺旋/β-发夹与膜的相互作用在原子水平上。取向NMR观测的系综动力学将提供膜蛋白动力学的深入理解。由于单次跨膜螺旋的膜蛋白非常丰富，本项目亦将提供一个定量方法，以了解它们在膜中的结构和动力学。本项目旨在通过提供（1）螺旋/β-发夹约束势和定向NMR约束势作为研究工具，以及（2）CHARMM-GUI网站（http：www.charmm-gui.org）作为学生和研究人员的教育/研究工具。限制电位可以应用于其功能涉及螺旋/β-发夹运动的各种肽/蛋白质。由此产生的系综动力学协议，以确定蛋白质的结构和动力学从对齐的NMR样品数据将是一个有用的工具，NMR社区。CHARMM-GUI网站向公众开放，并将进一步开发，为学生和研究人员提供各种生物分子模拟和建模工具的基于网络的图形用户界面（GUI）。除了研究生培训，两名本科生将参与这个项目，以促进他们在计算生物物理学的兴趣。该项目将通过出版研究成果和参加讲习班等外联活动，提高公众的科学素养。

Despite considerable advances in both experimental and computational methods to study biologically-important membrane proteins, it is still challenging to determine their structures and dynamics in biological membranes. This project seeks to characterize dynamics and orientation of helix/beta-hairpin in membrane environments by calculating the potentials of mean force (PMFs) along their orientations and by performing ensemble dynamics with available orientational NMR observables. This research will provide novel insights into the following important biophysical questions. Why does a single transmembrane helix or beta-hairpin have specific orientations in membranes? What are the roles of hydrogen bonds, close packing, and beta-hairpin-lipid interactions in beta-hairpin associations in membranes? What is the dynamic information embedded in NMR data obtained from aligned samples or what is the influence of helix dynamics on such observables? The PMF calculations and their decomposition into various microscopic contributions will enrich our understanding of the molecular basis of transmembrane helix/beta-hairpin orientation and interaction by determining the delicate balance of forces governing helix/beta-hairpin interactions with membranes at the atomic level. The ensemble dynamics with orientational NMR observables will provide the in-depth understanding of membrane protein dynamics. Given the abundance of membrane proteins with a single-pass transmembrane helix, this project will also provide a quantitative approach to understand their structure and dynamics in membranes.This project seeks to foster synergistic scientific research and education in the field of computational biophysics by providing (1) the helix/beta-hairpin restraint potentials and the orientational NMR restraint potentials as research tools, and (2) the CHARMM-GUI website (http://www.charmm-gui.org) as an education/research tool for students and researchers. The restraint potentials can be applied to various peptides/proteins whose functions involve helix/beta- hairpin movements. The resulting ensemble dynamics protocol to determine protein structure and dynamics from aligned NMR sample data will be a useful tool for the NMR community. The CHARMM-GUI website is open to the public and will be further developed to provide students and researchers with a web-based graphical user interface (GUI) for various biomolecular simulation and modeling tools. In addition to graduate student training, two undergraduate students will be involved in this project to promote their interests in computational biophysics. This project will raise the scientific literacy of the public by outreach activities such as publication of research results and participation of workshops.