Modeling Hydrophobic and Hydrophilic Interactions

描述（由申请人提供）：疏水性在蛋白质折叠中的重要性是公认的。一个特别令人兴奋的现象是突然的大规模去湿转变，发生两个大的疏水溶质被带到一起。但是，像蛋白质这样的生物系统容易发生这种干燥转变吗？我们最近已经证明，野生型蜂毒肽四聚体确实表现出快速去湿转变，并且自发干燥是某些疏水残基的敏感突变。对BphC酶的类似研究表明，塌陷不是由干燥转变引起的。在这个建议中，我们的目标是（a）调查的疏水基团的拓扑结构的敏感性;（B）确定与干燥相关的关键序列;（c）设计生物信息学工具，以确定干燥过渡的候选蛋白质;（d）调查野生型蛋白质是否优化去湿;和（e）设计算法，通过减少蛋白质和水之间的吸引力，加快蛋白质折叠。疏水相互作用也被认为与酶调节密切相关，酶调节由小分子（配体）和蛋白质的相互作用调节。初步结果表明，凹结合口袋导致增加的疏水性，因此，溶剂化的蛋白质-配体复合物是非常敏感的表面拓扑结构。我们目前正在进行一项详细的研究，使用所有的原子分子动力学来验证这些初步的结果，这表明添加条款的疏水封闭隐式溶剂模型。合理药物设计的另一个主要障碍是缺乏现实的力场。在详细的QM/MM研究中，我们最近证明了当肽经历构象变化或移动到不同环境中时诱导原子电荷的意义。校正该效应显示出显著改善配体与蛋白质的预测结合亲和力。我们建议开发第二代可极化力场，除了诱导偶极子，还包括诱导电荷。这个项目将整合我们现有的两个力场，分别解释波动电荷和波动偶极子。也许最重要的是，高分辨率蛋白质预测的关键瓶颈似乎是缺乏足够的构象采样。该提案的一个高度优先事项是为生物系统（如水溶液中的蛋白质）开发改进的采样方法。

DESCRIPTION (provided by applicant): The importance of hydrophobicity in protein folding is universally recognized. A particularly exciting phenomenon is the sudden large scale de-wetting transition that occurs as two large hydrophobic solutes are brought together. But are biological systems like proteins prone to such drying transitions? We have recently demonstrated that the wild-type Melittin tetramer indeed exhibits a fast de-wetting transition, and that spontaneous drying is sensitive mutation of certain hydrophobic residues. A similar study of the BphC enzyme revealed that the collapse is not induced by a drying transition. In this proposal, we aim to (a) investigate sensitivity to the topology of the hydrophobic groups; (b) identify key sequences associated with drying; (c) design bioinformatics tools to identify protein candidates for drying transitions; (d) investigate whether wild-type proteins are optimized for de-wetting; and (e) design algorithms for speeding up protein folding by reducing the attractive forces between protein and water. Hydrophobic interactions are also expected to be closely tied to enzymatic modulation, which is regulated by the interaction of a small molecule (ligand) and a protein. Initial results indicate that concave binding pockets lead to increased hydrophobicity and, thus, solvated protein-ligand complexes are very sensitive to surface topology. We are currently undertaking a detailed study using all atom molecular dynamics to verify these initial results, which suggest adding terms for hydrophobic enclosure to implicit solvent models. Another major impediment to rational drug design is the lack of realistic force fields. In a detailed QM/MM study, we have recently demonstrated the significance of induced atomic charges when a peptide undergoes conformational changes or moves into different environments. Correcting for this effect was shown to significantly improve the predicted binding affinities of ligands to proteins. We propose to develop a second generation polarizable force field that incorporates induced charges in addition to induced dipoles. This project will integrate two of our existing force fields, which account for fluctuating charges and fluctuating dipoles separately. Perhaps most significantly, it appears that the critical bottleneck in high-resolution protein prediction is the lack of adequate conformational sampling. It is a high priority of this proposal to develop improved sampling methods for biological systems such as proteins in aqueous solution.