Toward Practical, Rigorous Binding Affinity Calculations

描述(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，以及非相加效应，这不能适当地包括在更快、更近似的估计中。然而，这种理想的计算超出了当今计算资源的极限，因此产生的实际影响有限。此外，严格的亲和力估计也会受到假设力场误差的影响，这可能会导致即使在进行设计良好、收敛良好的计算时也不准确。该建议旨在采取重要步骤来克服这些障碍，从而使严格的亲和力评估成为建模师工具包中实用、可靠的部分。计算成本的问题将通过创新、有效的方法来解决；准确性将通过使用标准力场和可极化力场来解决；最后，将使用新的终点(非炼金术)方法和新的构象采样方案来解决分子灵活性问题。雌激素受体是一个真正体现了亲和力计算的所有挑战的系统，拥有非常多样化的配体，其中一些会引起受体构象的巨大变化。除了其深远的临床重要性，雌激素受体是理解核激素受体结合现象的关键模型系统。我们改进严格亲和力计算的策略将在雌激素受体系统中进行，在一系列日益复杂的任务中进行。首先，将在溶液中研究雌激素受体配体，然后在简化的受体结合位置模型中进行研究，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.