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得到了普遍的认可。一个特别令人兴奋的现象是突然发生的大规模去湿转变，这种转变发生在两个大型疏水溶质聚集在一起时。但是，像蛋白质一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，野生型蜂毒素四聚体确实表现出快速的去湿转变，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，坍塌不是由干燥转变引起的。在这项建议中，我们的目标是：(A)研究疏水基团对拓扑的敏感性；(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候选的干燥转变蛋白质；(D)研究野生型蛋白质是否针对去湿进行了优化；以及(E)设计通过减少蛋白质与水之间的引力来加快蛋白质折叠的算法。疏水相互作用也被认为与酶的调节密切相关，酶的调节由小分子(配体)和蛋白质的相互作用调节。初步结果表明，凹陷的结合口袋导致疏水性增加，因此，溶剂化的蛋白质-配体复合体对表面拓扑非常敏感。我们目前正在进行一项详细的研究，使用全原子分子动力学来验证这些初步结果，这些结果建议在隐含的溶剂模型中添加疏水封闭项。合理药物设计的另一个主要障碍是缺乏现实的力场。在一项详细的QM/MM研究中，我们最近证明了当一个肽经历构象变化或进入不同的环境时，诱导原子电荷的重要性。对这一效应的校正表明，显著提高了预测的配体与蛋白质的结合亲和力。我们建议发展第二代可极化力场，除了感应偶极子外，还包括感应电荷。这个项目将整合我们现有的两个力场，这两个力场分别解释了波动的电荷和波动的偶极子。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。为水溶液中的蛋白质等生物系统开发改进的采样方法是这项建议的一个高度优先事项。

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.