Drug Binding Free Energies with Implicit Solvent Methods

描述(申请人提供)：1)采用标准的隐含溶剂模型，结合原子生物分子模型和现代采样技术，试图直接计算一系列蛋白质-配体体系中配体结合的绝对自由能。2)发展统计方法，以确定不同的采样技术中，如果有的话，哪些能够真正能够为一系列相关体系得出精确的结合络合物的自由能。3)利用这些结果来确定可以改进隐含的溶剂和原子生物分子模型以更好地拟合各种配体蛋白质络合物的结合能和结构的方法。这项研究对合理的药物设计，进而对所有的医学都有重要的意义。如果生物分子模拟的预测能力能够显著提高，并且这些方法的效率提高，那么将导致药物开发的总成本显著降低。

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.