Calculation of absolute protein-ligand binding free energy from computer simulations
Calculation of absolute protein-ligand binding free energy from computer simulations
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DOI：
10.1073/pnas.0409005102
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发表时间：
2005-05-10
影响因子：
11.1
通讯作者：
Roux, B
中科院分区：
文献类型：
--
作者：
Woo, HJ;Roux, B
在平均力势的基础上，提出了计算柔性配体与蛋白质受体的平衡结合常数的一般方法。整个过程被分解为几个阶段，可以分别计算：首先通过施加偏置电势将主体中的自由配体限制为其在结合状态、位置和取向中所采用的构象，然后将其转换到结合位置，在那里完全释放。构象抑制势基于多肽坐标相对于其在结合络合物中的平均构象的均方根偏差。利用平均力技术中的自由能微扰势，通过选取合适的序参数，计算了各阶段的自由能贡献。本方法避免了传统的双去偶联方案中需要将配体与其周围(主体溶剂和受体蛋白)去偶联的需要。当配体的溶剂化自由能很大时，本公式被认为特别有用。作为应用，计算了磷酸化酪氨酸肽pYEEI与人Lck的Src同源2结构域的平衡结合常数。计算结果与实验值吻合较好。
A general methodology for calculating the equilibrium binding constant of a flexible ligand to a protein receptor is formulated on the basis of potentials of mean force. The overall process is decomposed into several stages that can be computed separately: the free ligand in the bulk is first restrained into the conformation it adopts in the bound state, position, and orientation by applying biasing potentials, then it is translated into the binding site, where it is released completely. The conformational restraining potential is based on the root-mean-square deviation of the peptide coordinates relative to its average conformation in the bound complex. Free energy contributions from each stage are calculated by means of free energy perturbation potential of mean force techniques by using appropriate order parameters. The present approach avoids the need to decouple the ligand from its surrounding (bulk solvent and receptor protein) as is traditionally performed in the double-decoupling scheme. It is believed that the present formulation will be particularly useful when the solvation free energy of the ligand is very large. As an application, the equilibrium binding constant of the phosphotyrosine peptide pYEEI to the Src homology 2 domain of human Lck has been calculated. The results are in good agreement with experimental values.