Simple, intuitive calculations of free energy of binding for protein-ligand complexes. 1. Models without explicit constrained water
Simple, intuitive calculations of free energy of binding for protein-ligand complexes. 1. Models without explicit constrained water
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DOI：
10.1021/jm0200299
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发表时间：
2002-06-06
影响因子：
7.3
通讯作者：
Mozzarelli, A
中科院分区：
文献类型：
--
作者：
Cozzini, P;Fornabaio, M;Mozzarelli, A
预测蛋白质与配体之间的结合亲和力是计算生物化学和药物发现中最具挑战性的问题之一。虽然分子力学方法通常可以获得对结合的熵贡献，但熵贡献更难以估计。我们描述和应用一个相对简单和直观的计算程序，用于估计由17个已知的三维结构的蛋白质形成的53个蛋白质-配体复合物的结合自由能，其特征在于不同的活性位点极性。HINT是一种基于小有机分子实验LogP（o/w）值的软件模型，用于评估和评分蛋白质与配体之间的所有原子-原子亲水相互作用。这些总评分（H-TOTAL）先前已显示与蛋白质-蛋白质相互作用的DeltaG（相互作用）相关，在本研究中与蛋白质-配体复合物的DeltaG（结合）相关，标准误差为+/-2.6 kcal mol（-1），公式为DeltaG（结合）= -0.00195 H-TOTAL-5.543。一个更复杂的模型，利用分类（按相互作用类别）的HINT分数，产生+/-1.8 kcal mol（-1）的上级标准误差。结果表明，在同一蛋白质结合位点的配体家族内，可以获得更好的模型，标准误差接近+/-1.0 kcal mol（-1）。还描述了制备用于亲水分析的晶体学模型的标准化方法。特别注意的是配体的电离状态和pH条件下，结合测量之间的关系。来源和潜在的补救措施的实验和建模误差影响预测的DeltaG（绑定）进行了讨论。
The prediction of the binding affinity between a protein and ligands is one of the most challenging issues for computational biochemistry and drug discovery. While the enthalpic contribution to binding is routinely available with molecular mechanics methods, the entropic contribution is more difficult to estimate. We describe and apply a relatively simple and intuitive calculation procedure for estimating the free energy of binding for 53 protein-ligand complexes formed by 17 proteins of known three-dimensional structure and characterized by different active site polarity. HINT, a software model based on experimental LogP(o/w) values for small organic molecules, was used to evaluate and score all atom-atom hydropathic interactions between the protein and the ligands. These total scores (H-TOTAL), which have been previously shown to correlate with DeltaG(interaction) for protein-protein interactions, correlate with DeltaG(binding) for protein-ligand complexes in the present study with a standard error of +/-2.6 kcal mol(-1) from the equation DeltaG(binding) = -0.00195 H-TOTAL -5.543. A more sophisticated model, utilizing categorized (by interaction class) HINT scores, produces a superior standard error of +/-1.8 kcal mol(-1). It is shown that within families of ligands for the same protein binding site, better models can be obtained with standard errors approaching +/-1.0 kcal mol(-1). Standardized methods for preparing crystallographic models for hydropathic analysis are also described. Particular attention is paid to the relationship between the ionization state of the ligands and the pH conditions under which the binding measurements are made. Sources and potential remedies of experimental and modeling errors affecting prediction of DeltaG(binding) are discussed.