Toward Practical, Rigorous Binding Affinity Calculations

描述（由申请人提供）：基于统计力学的理想、严格的结合亲和力计算将充分考虑配体和受体（蛋白质）的灵活性以及非累加效应，这些效应无法正确地纳入更快、更近似的估计值中。然而，这种理想的计算突破了当今计算资源的极限，因此实际影响有限。此外，严格的亲和力估计还遭受假设力场中的误差，这可能导致不准确，即使在执行良好设计、良好收敛的计算时。该提案旨在采取重要步骤克服这些障碍，从而使严格的亲和力估计成为建模工具包中实用，可靠的一部分。计算成本的问题将得到解决的创新，有效的方法;准确性将通过使用标准和极化力场解决;最后，分子的灵活性将使用新的端点（非“炼金术”）的方法和一个新的构象采样计划。雌激素受体是一个系统，真正体现了亲和力计算的所有挑战，具有很大的多样性的配体，其中一些诱导一个大的受体构象变化。除了其深远的临床意义，雌激素受体是一个关键的模型系统，了解结合现象的核激素受体。我们的策略，以提高严格的亲和力计算将追求在雌激素受体系统中，在一系列的任务日益复杂。首先，雌激素受体配体将在溶液中进行研究，然后在受体结合位点的简化模型中进行研究，最后将研究整个系统。与当地的实验合作者，我们将尝试工程化合物的潜在临床重要性。成功的计算方法将在广泛可用的软件包中实施。

DESCRIPTION (provided by applicant): Ideal, rigorous binding affinity computations, based on statistical mechanics, would fully account for ligand and receptor (protein) flexibility, as well as non-additive effects, which cannot properly be included in faster, more approximate estimates. Such ideal calculations, however, push the limits of present-day computational resources, and therefore have had limited practical impact. Furthermore, rigorous affinity estimates also suffer from errors in the assumed forcefields, which may lead to inaccuracies even when well-designed, well- converged calculations are performed. This proposal aims to take important steps toward overcoming these obstacles, and thus to make rigorous affinity estimation a practical, reliable part of the modeler's toolkit. The issue of computational cost will be addressed with innovative, efficient methods; accuracy will be addressed by the use of both standard and polarizable forcefields; and, lastly, molecular flexibility will be addressed using novel end-point (non- "alchemical") methods and a new conformational sampling scheme. The estrogen receptor is a system which truly embodies all the challenges of affinity calculations, possessing a great diversity of ligands, some of which induce a large receptor conformational change. Beyond its far- reaching clinical importance, the estrogen-receptor is a key model system for understanding binding phenomena in nuclear hormone receptors. Our strategies for improving rigorous affinity calculations will be pursued in the estrogen receptor system, in a series of tasks of increasing complexity. First, estrogen receptor ligands will be studied in solution, then in simplified models of the receptor binding site, and finally the full system will be investigated. With a local experimental collaborator, we will attempt to engineer compounds of potential clinical importance. Successful computational approaches will be implemented in widely available software packages.