Modeling Hydrophobic and Hydrophilic Interactions

描述(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核心重要性的重大挑战。水分子参与生物过程，包括与蛋白质的配体结合，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。基于我们在开发取代溶剂功能方法学(DSM)方面的最新进展，我们建议开发准确计算蛋白质-配体结合亲和力的方法。我们建议将我们的“水图”方法发展成一个实用的药物化学工具，将其扩展到具有亲水性、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的库中。这项工作是与哥伦比亚大学弗里斯纳小组正在进行的卓有成效的合作的一部分。为了加快这项研究，我们建议将我们的新的有色噪声多时间步长MD算法(CN-RESPA)与我们的副本交换与溶质回火(REST)算法以及现有的；-跳跃自由能微扰算法(；-Hopping FEP)相结合，为上述研究中计算结合效率和采样构象状态提供非常强大的方法。亨廷顿氏病是由含有CAG密码子的区域的遗传扩张引起的，这导致亨廷顿蛋白的聚谷氨酰胺束长度增加，随后触发了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核快速形成聚集的低聚物，最终形成特征性的淀粉样蛋白，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、寿命长的PolyQ双背结构的例子，这些结构在机械上对大拉力具有弹性(正如在AFM实验中看到的那样)。我们建议使用Anton等功能强大的计算机进行足够长的分子模拟，以确定聚Q的机械弹性错误折叠构象的结构，探索残基-水和残基-残基相互作用之间的平衡，以更好地理解为什么多Q及其高极性侧链基团形成如此紧密的结构，然后深入了解多聚Q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.