Drug Binding Free Energies with Implicit Solvent Methods

描述（申请人提供）：1)采用标准隐式溶剂模型，结合原子生物分子模型和现代采样技术，尝试直接评估一系列蛋白质-配体体系中配体结合的绝对自由能。2)开发统计方法，以确定各种采样技术中哪一种（如果有的话）能够真正地为一系列相关系统产生结合配合物的精确自由能。3)利用这些结果确定隐式溶剂和原子生物分子模型可以改进的方法，以更好地适应各种配体蛋白质复合物的结合能和结构。这项研究对合理的药物设计，乃至整个医学都有重要的影响。如果能够显著提高生物分子模拟的预测能力，提高这些方法的效率，将会显著降低药物开发的总成本。

DESCRIPTION (provided by applicant): 1) To take standard implicit solvent models, combined with atomistic biomolecular models and modern sampling techniques, and attempt to directly evaluate the absolute free energy of ligand binding in a range of protein-ligand systems. 2) To develop statistical methods to identify of which, if any, of various sampling techniques are able to truly able to yield precise free energies of binding complexes for a range of relevant systems. 3) To use these results to identify ways in which the implicit solvent and atomistic biomolecular models can be improved to better fit the binding energies and structures for a wide variety of ligand protein complexes. This research has important consequences for rational drug design, and consequently all of medicine. If the predictive ability of biomolecular simulations can be significantly improved, and the efficiency of these methods increased, it will result in significantly lowered total costs of drug development.