Computational Analysis of Peptide/lipid Interactions and Organization at Membrane Surfaces

该项目的重点是开发数值程序，用于计算多肽与膜界面关联的物理基础，脂质横向再分布所涉及的静电力，以及基于比过去使用的更现实的模型的膜系统的详细静电特性。本项目基于两个主要假设：1)物理力-静电和疏水-介导两亲肽的膜结合：静电相互作用发生在碱性残基和酸性磷脂之间，疏水相互作用通过划分到膜的极性头基区域的芳香残基介导。2)非特异性静电相互作用为所观察到的多价酸性磷脂被膜吸附多肽上与这些基本结构域相对应的碱性残基簇横向隔离提供了驱动力。有限差分泊松-玻尔兹曼（FDPB）方法基于对水溶液的连续描述和对大分子的更详细的原子级描述，在重现不穿透膜界面的简单碱性肽的结合自由能的实验测量能力方面取得了显著成功。在这里，连续体方法将扩展到含有碱性和芳香残基的肽，它们确实能穿透膜界面。此外，通过将膜的分子动力学模拟快照纳入FDPB计算，将开发更现实的肽/膜系统的结构和理论模型。与所有层次的实验进行比较将有助于改进理论方法，并为实验研究提供有价值的输入。这里描述的研究是基于计算方法，最终目的是提供外周蛋白和膜之间相互作用的详细理论描述。这项研究是重要的，因为肽/膜相互作用的一般领域的意义，因为提出的许多问题只能用计算方法来解决。该项目涉及生物物理工具的联合开发和应用，以描述以前没有使用计算技术研究过的问题，以及计算和实验工作之间的密切协作互动。首席研究员参与了许多研究生项目，如化学生物学项目，生物化学和结构生物学研究生项目，以及信号转导细胞和分子生物物理学的Keck项目。通过诸如此类的项目开发的计算和研究基础设施有助于丰富研究生培训环境。

The focus of this project is the development of numerical procedures for calculating the physical basis of the association of peptides with the membrane interface, the electrostatic forces involved in lateral redistribution of lipids, and detailed electrostatic properties of membrane systems based on more realistic models than have been used in the past. This project is based on two main hypotheses: 1) Physical forces-electrostatics and hydrophobicity-mediate the membrane association of amphipathic peptides: the electrostatic interactions occur between basic residues and acidic phospholipids, and the hydrophobic interactions are mediated via aromatic residues which partition into the polar headgroup region of the membrane. 2) Nonspecific electrostatic interactions provide the driving force for the observed lateral sequestration of multivalent acidic phospholipids by clusters of basic residues on membrane-adsorbed peptides corresponding to these basic domains. The finite difference Poisson-Boltzmann (FDPB) method, which is based on a continuum description of the aqueous solvent and a more detailed, atomic-level description of the macromolecules, has been remarkably successful in its ability to reproduce experimental measurements of the binding free energies of simple basic peptides that do not penetrate the membrane interface. Here, the continuum approach will be extended to peptides containing basic and aromatic residues that do penetrate the membrane interface. In addition, more realistic structural and theoretical models of peptide/membrane systems will be developed by incorporating snapshots from molecular dynamics simulations of membranes into FDPB calculations. Comparison with experiments at all levels will allow refinement of the theoretical methodology and provide valuable input to the experimental studies. The research described here is based on computational approaches and aims ultimately to provide a detailed theoretical description of the interactions between peripheral proteins and membranes. This research is important both because of the significance of the general area of peptide/membrane interactions and because many of the questions posed can only be approached with computational methods. This project involves the combined development and application of biophysical tools to describe problems that have not previously been studied with computational techniques and close collaborative interactions between computational and experimental work. The principal investigator is involved in a number of graduate programs such as the Program for Chemical Biology, the Biochemistry and Structural Biology Graduate Program, and the Keck Program in Cellular and Molecular Biophysics of Signal Transduction. The computational and research infrastructure being developed through projects such as this one is contributing to the enrichment of the graduate training environment.