The Binding Energy Distribution Analysis Method (BEDAM) for the Estimation of Protein-Ligand Binding Affinities.
The Binding Energy Distribution Analysis Method (BEDAM) for the Estimation of Protein-Ligand Binding Affinities.
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DOI：
10.1021/ct1002913
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发表时间：
2010-09-14
影响因子：
5.5
通讯作者：
Levy, Ronald M.
中科院分区：
文献类型：
--
作者：
Gallicchio, Emilio;Lapelosa, Mauro;Levy, Ronald M.
本文提出了结合能分布分析法（BEDAM），用于计算隐式溶剂化条件下受体-配体标准结合自由能。该方法是基于一个完善的统计力学理论的分子缔合。结果表明，在隐式溶剂化的背景下，该理论是同源的溶剂化热力学的测试粒子方法与溶质-溶剂的蛋白质-配体复合物的有效结合能表示的潜力。因此，在BEDAM中，结合常数是通过在正则系综中获得的结合能的概率分布的加权积分来计算的，其中配体位于结合位点中，但受体和配体仅与溶剂连续体相互作用。它示出的结合能分布编码的结合的所有物理效应。结合焓和熵之间的平衡在我们的形式主义中被看作是有利和不利的结合模式之间的平衡，通过结合能分布函数的归一化来耦合。基于AGBNP 2隐式溶剂模型、并行哈密顿副本交换采样和直方图重加权，开发了一种有效的结合能分布计算协议。说明了该方法对T4溶菌酶受体的L99 A和L99 A/M102 Q突变体的一组已知结合剂和非结合剂的应用。该方法是能够区分无错误的粘合剂从非粘合剂，和计算的标准结合自由能的粘合剂被发现是在良好的协议与实验测量。结果分析表明，这些系统的结合亲和力反映了跨越广泛的结合能的多种构象的贡献。
The Binding Energy Distribution Analysis Method (BEDAM) for the computation of receptor-ligand standard binding free energies with implicit solvation is presented. The method is based on a well established statistical mechanics theory of molecular association. It is shown that, in the context of implicit solvation, the theory is homologous to the test particle method of solvation thermodynamics with the solute-solvent potential represented by the effective binding energy of the protein-ligand complex. Accordingly, in BEDAM the binding constant is computed by means of a weighted integral of the probability distribution of the binding energy obtained in the canonical ensemble in which the ligand is positioned in the binding site but the receptor and the ligand interact only with the solvent continuum. It is shown that the binding energy distribution encodes all of the physical effects of binding. The balance between binding enthalpy and entropy is seen in our formalism as a balance between favorable and unfavorable binding modes which are coupled through the normalization of the binding energy distribution function. An efficient computational protocol for the binding energy distribution based on the AGBNP2 implicit solvent model, parallel Hamiltonian replica exchange sampling and histogram reweighting is developed. Applications of the method to a set of known binders and non-binders of the L99A and L99A/M102Q mutants of T4 lysozyme receptor are illustrated. The method is able to discriminate without error binders from non-binders, and the computed standard binding free energies of the binders are found to be in good agreement with experimental measurements. Analysis of the results reveals that the binding affinities of these systems reflect the contributions from multiple conformations spanning a wide range of binding energies.
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影响因子：
15
作者：
Abel, Robert;Young, Tom;Friesner, Richard A.
通讯作者：
Friesner, Richard A.
影响因子：
5.5
作者：
Felts, Anthony K.;Gallicchio, Emilio;Levy, Ronald M.
通讯作者：
Levy, Ronald M.
影响因子：
2.9
作者：
Felts, AK;Harano, Y;Levy, RM
通讯作者：
Levy, RM
影响因子：
7.3
作者：
Graves, AP;Brenk, R;Shoichet, BK
通讯作者：
Shoichet, BK
DOI：
10.1021/jp807701h
发表时间：
2009-02-26
期刊：
The journal of physical chemistry. B
影响因子：
--
作者：
Deng Y;Roux B
通讯作者：
Roux B