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，当两个大的疏水溶质聚集在一起时，会发生突然的大规模脱湿转变。但是，像蛋白质这样的生物系统是否容易发生这种干燥转变呢？我们最近证明了野生型蜂毒蛋白四聚体确实表现出快速的脱湿转变，而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，这种坍塌不是由干燥转变引起的。在这个提议中，我们的目标是(a)研究对疏水基团拓扑结构的敏感性；(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)研究野生型蛋白是否适合脱湿；(e)设计算法，通过减少蛋白质和水之间的吸引力来加速蛋白质折叠。疏水相互作用也被认为与酶调节密切相关，酶调节是由小分子（配体）和蛋白质的相互作用调节的。初步结果表明，凹结合口袋导致疏水性增加，因此，溶剂化的蛋白质配体复合物对表面拓扑结构非常敏感。我们目前正在进行一项详细的研究，使用所有原子分子动力学来验证这些初步结果，这些结果建议在隐式溶剂模型中添加疏水外壳的术语。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，我们最近证明了当肽经历构象变化或进入不同环境时诱导原子电荷的重要性。校正这种效应被证明可以显著提高配体对蛋白质的预测结合亲和力。我们建议发展第二代极化力场，除了诱导偶极子外，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。该建议的优先事项是开发改进的生物系统采样方法，如水溶液中的蛋白质。

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.