Effective Energy Functions for Proteins in Lipid Membranes

这个项目的目标是开发一个准确的和计算效率高的膜分析隐式溶剂化模型。该模型的初始版本（IMM1）最近通过对含水蛋白质的隐式溶剂化模型（EEF1）的扩展而提出。IMM1预测合理的膜插入自由能，区分跨膜和界面结合肽，并提供膜蛋白稳定的分子动力学模拟。该项目旨在通过测试IMM1的一些关键假设和纳入目前缺少的几个物理要素，提高其可靠性和扩大其适用性。具体而言，本项目涉及：a.通过与连续静电计算的比较来测试静电筛选模型，b.扩展到具有水孔的膜蛋白，如孔或离子通道，c.添加具有不同溶剂性质的单独脂质头基团区域，d.结合偶极子、表面和跨膜电位引起的静电效应，校正现有实验数据，定量预测多肽与膜的结合自由能。这项工作的结果将有助于理解膜蛋白结构的能量决定因素，从序列中预测膜蛋白结构，以及研究膜蛋白的构象变化如何与它们的功能联系起来。这些模型将提供给学术界和制药业的研究界。这项研究将在一所大学进行，其中60%的学生属于代表性不足的群体，本科生大量参与研究。

The goal of this project is to develop an accurate and computationally efficient analytical implicit solvation model for membranes. An initial version of such a model (IMM1) has been recently proposed by extension of an implicit solvation model for aqueous proteins (EEF1). IMM1 predicts reasonable membrane insertion free energies, discriminates transmembrane from interfacially binding peptides, and gives stable molecular dynamics simulations of membrane proteins. This project aims to enhance the reliability and extend the applicability of IMM1 by testing some of its key assumptions and by incorporating several physical elements that are now missing. Specifically, this project involves: a. testing of the electrostatic screening model by comparison to continuum electrostatics calculations, b. extension to membrane proteins with an aqueous pore, such as porins or ion channels , c. addition of a separate lipid headgroup region with distinct solvent properties, d. incorporation of electrostatic effects arising from the dipole, surface, and transmembrane potentials, and e. calibration to available experimental data for quantitative prediction of binding free energies of peptides to membranes. The outcome of this work will be useful for understanding the energetic determinants of membrane protein structure, prediction of membrane protein structure from sequence, and studies of how conformational changes in membrane proteins are linked to their function. The models will be made available to the research community in both academia and the pharmaceutical industry. This research will be carried out at an institution where 60% of the students belong to underrepresented groups and undergraduates are heavily involved in research.