Toward Practical, Rigorous Binding Affinity Calculations

描述（由申请人提供）：理想的，严格的结合亲和力计算，基于统计力学，将充分考虑配体和受体（蛋白质）的灵活性，以及非加性效应，这些不能正确地包括在更快，更近似的估计中。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，严格的亲和估计也会受到假设力场中的误差的影响，这可能导致即使在设计良好、收敛良好的计算中也不准确。这个建议的目的是采取重要的步骤来克服这些障碍，从而使严格的亲和估计成为建模者工具包的一个实用的、可靠的部分。计算成本的问题将以创新、有效的方法解决；准确性将通过使用标准力场和极化力场来解决；最后，分子柔韧性将使用新的端点（非“炼金术”）方法和新的构象采样方案来解决。雌激素受体是一个真正体现亲和计算的所有挑战的系统，它拥有非常多样化的配体，其中一些配体会引起很大的受体构象变化。除了其深远的临床意义外，雌激素受体是理解核激素受体结合现象的关键模型系统。我们的策略，以提高严格的亲和计算将追求在雌激素受体系统，在一系列的任务日益复杂。首先，将在溶液中研究雌激素受体配体，然后在受体结合位点的简化模型中进行研究，最后对整个系统进行研究。与当地的实验合作者一起，我们将尝试设计具有潜在临床重要性的化合物。成功的计算方法将在广泛可用的软件包中实现。

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.