Toward Rapid Rigorous Calculations of Binding Affinities

描述(由申请人提供)： 这项研究建议的目标是进一步发展快速、严格的结合亲和力计算。长期目标是提供适用于药物设计的化合物虚拟筛选的技术。现有用于结合亲和力计算的严格方法需要长时间的模拟，因此对于虚拟筛选是不可行的。所提出的方法将从一系列分子和蛋白质系统的非平衡计算机模拟中计算平衡结合亲和力。其目的是：(I)制定最佳使用标准非平衡方法的实用指南，以及非平衡方法和平衡方法之间的仔细比较；(Ii)在Zuckerman、Woolf和申请人工作的基础上，将非平衡外推技术扩展到蛋白质-配体系统。这些方法克服了标准非平衡计算的收敛性能较差的缺点；{iii)扩展了单一模拟路径抽样方法，将分子，然后是蛋白质-配体体系包括在TINKER软件包中。该方法由申请人和Zuckerman开发，使用路径抽样来有效地计算基于非平衡的亲和力估计。

DESCRIPTION (provided by applicant): The objective of this research proposal is to further the development of rapid, rigorous calculations of binding affinities. The long-term goal is to provide techniques suitable for virtual screening of compounds for drug design. Existing rigorous methods for binding affinity calculations require long simulation and thus are not feasible for virtual screening. The proposed methods will calculate equilibrium binding affinities from non-equilibrium computer simulations for a range of molecular and protein systems. The aims are: (i) Develop practical guidelines for optimal use of standard non-equilibrium methods, along with a careful comparison between non-equilibrium and equilibrium methods; (ii) Extend non-equilibrium extrapolation techniques to protein-ligand systems, building on work by Zuckerman, Woolf and the applicant. These approaches overcome poor convergence properties of standard non-equilibrium calculations; {iii) Extend the single-simulation path sampling method to include molecular, then protein-ligand, systems within the TINKER software package. Developed by the applicant and Zuckerman, the method employs path-sampling to efficiently compute non-equilibrium-based affinity estimates.