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首页> 外文期刊>Journal of Molecular Biology >Predicting absolute ligand binding free energies to a simple model site
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Predicting absolute ligand binding free energies to a simple model site

机译：预测绝对配体结合自由能到一个简单的模型位点

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摘要

A central challenge in structure-based ligand design is the accurate prediction of binding free energies. Here we apply alchemical free energy calculations in explicit solvent to predict ligand binding in a model cavity in T4 lysozyme. Even in this simple site, there are challenges. We made systematic improvements, beginning with single poses from docking, then including multiple poses, additional protein conformational changes, and using an improved charge model. Computed absolute binding free energies had an RMS error of 1.9 kcal/mol relative to previously determined. experimental values. In blind prospective tests, the methods correctly discriminated between several true ligands and decoys in a set of putative binders identified by docking. In these prospective tests, the RMS error in predicted binding free energies relative to those subsequently determined experimentally was only 0.6 kcal/mol. X-ray crystal structures of the new ligands bound in the cavity corresponded closely to predictions from the free energy calculations, but sometimes differed from those predicted by docking. Finally, we examined the impact of holding the protein rigid, as in docking, with a view to learning how approximations made in docking affect accuracy and how they may be improved. (c) 2007 Elsevier Ltd. All rights reserved.
机译：基于结构的配体设计的一个主要挑战是结合自由能的准确预测。在这里，我们在明确的溶剂中应用炼金术自由能计算来预测T4溶菌酶模型腔中的配体结合。即使在这个简单的站点中，也存在挑战。我们进行了系统的改进，从对接中的单个姿势开始，然后包括多个姿势，其他蛋白质构象更改以及使用改进的电荷模型。计算的绝对结合自由能相对于先前确定的RMS误差为1.9 kcal / mol。实验值。在盲目的前瞻性测试中，这些方法正确区分了通过对接识别出的一组推定结合物中的几种真实配体和诱饵。在这些前瞻性测试中，相对于随后实验确定的预测结合自由能的RMS误差仅为0.6 kcal / mol。结合在空腔中的新配体的X射线晶体结构与自由能计算的预测非常接近，但有时与对接预测的结果不同。最后，我们研究了将蛋白质刚性固定（如对接）的影响，以了解对接中的近似值如何影响准确性以及如何改进它们。 （c）2007 Elsevier Ltd.保留所有权利。

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