Modeling Hydrophobic and Hydrophilic Interactions

描述（由申请人提供）：生物过程通常依赖于配体与受体的结合，但相关结合自由能的准确计算仍然是基于结构的药物设计的一个重要挑战。水分子参与生物过程，包括配体与蛋白质的结合，以及蛋白质的机械稳定性和聚集。我们建议使用分子模拟和理论来更深入地了解水在上述过程中的作用。基于我们最近在开发一种取代溶剂功能方法学（DSM）方面的进展，我们建议开发精确计算蛋白质-配体结合亲和力的方法。我们建议将我们的“水图”方法扩展到具有亲水性、疏水性和中性残基混合物的异质蛋白质受体界面，并将其应用于受体和配体文库，从而使其成为药物化学的实用工具。这项工作是与哥伦比亚大学弗里斯纳小组正在进行的富有成效的合作的一部分。为了加速这一研究，我们提出将我们的新的彩色噪声多时间步MD算法（CN-RESPA）与我们的副本交换溶质回火（REST）算法和现有的；跳跃自由能摄动算法（-hopping FEP）为上述研究中计算结合效率和采样构象态提供了一种极其强大的方法。亨廷顿氏病是由含有CAG密码子的区域的遗传扩增引起的，该区域导致蛋白质亨廷顿蛋白的聚谷氨酰胺束长度增加，随后引发细胞毒性聚谷氨酰胺淀粉样纤维和斑块的形成。人们认为，单个罕见的错误折叠的聚谷氨酰胺多肽作为快速形成聚集寡聚物和最终特征淀粉样蛋白的细胞核，但结构生物学家一直无法确定这些错误折叠构象的结构。在初步的模拟中，我们发现了高度坍塌的长寿命polyQ双背结构的例子，这些结构对大拉力具有机械弹性（如在AFM实验中所见）。我们建议使用像ANTON这样强大的计算机进行足够长的分子模拟，以确定polyQ的机械弹性错误折叠构象的结构，探索残留物-水和残留物-残留物相互作用之间的平衡，以更好地理解为什么polyQ具有高极性侧链基团形成如此紧凑的结构，然后，深入了解polyQ在聚集过程中的构象转变。

DESCRIPTION (provided by applicant): Biological processes often depend on ligand binding to receptors yet accurate calculation of the associated binding free energy remains a significant challenge of central importance to structure-based drug design. Water molecules participate in biological processes, including ligand binding to proteins, and the mechanical stability and aggregation of proteins. We propose to use molecular simulations and theory to provide deeper insights into water's role in the above processes. We propose to develop methods for the accurate calculation of protein-ligand binding affinities based on our recent progress towards developing a displaced solvent functional methodology (DSM). We propose to develop our "WaterMap" method into a practical tool for medicinal chemistry, by extending it to heterogeneous protein receptor interfaces with mixtures of hydrophilic, hydrophobic and neutral residues and to apply it to libraries of receptors and ligands. This work is part of an ongoing fruitful collaboration with the Friesner group at Columbia. To expedite this research we propose to combine our new colored noise multiple time step MD algorithm (CN-RESPA) with our replica exchange with solute tempering (REST) algorithm and the existing ;-hopping free energy perturbation algorithm (;-hopping FEP) to provide an extremely powerful methodology for calculating binding efficiencies and sampling conformational states in the above research. Huntington's disease is caused by a genetic expansion of a region containing the CAG codon that leads to an increase in the length of the protein huntingtin's polyglutamine tract and a subsequent triggering of the formation of cytotoxic polyglutamine amyloid fibers and plaques. It is thought that a single rare misfolded polyglutamine polypeptide serves as a nucleus for the rapid formation of aggregated oligomers and finally the characteristic amyloid, but structural biologists have been unable to determine structures of these misfolded conformations. In preliminary simulations we found examples of highly collapsed long lived polyQ double-back structures that are mechanically resilient against large pulling forces (as is seen in AFM experiments). We propose to perform long enough molecular simulations using powerful computers like ANTON to pin down the structures of the mechanically resilient misfolded conformations of polyQ, to explore the balance between residue-water and residue-residue interactions to better understand why polyQ with its highly polar side-chain groups forms such compact structure, and, then, to get insights into conformational transitions of polyQ during aggregation.