Confine-and-release method: Obtaining correct binding free energies in the presence of protein conformational change
Confine-and-release method: Obtaining correct binding free energies in the presence of protein conformational change
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DOI：
10.1021/ct700032n
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发表时间：
2007-07-01
影响因子：
5.5
通讯作者：
Dill, Ken A.
中科院分区：
文献类型：
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作者：
Mobley, David L.;Chodera, John D.;Dill, Ken A.
自由能计算越来越多地被用于估计配体与蛋白质的绝对和相对结合自由能。然而，计算的自由能往往依赖于初始的蛋白质构象，这表明采样不完整。当蛋白质在配体结合时可以改变构象时尤其如此，因为与这些构象变化相关的自由能要么被忽略，要么被认为包含在计算中进行的采样中。在这里，我们表明，在一个模型蛋白质系统（T4溶菌酶的一个设计的结合位点）中，构象变化可以在计算的结合自由能中产生几千卡/摩尔的差异，如果系统在模拟时间尺度上保持在一个特定的亚稳态，构象变化在计算的结合自由能中被忽略。我们引入了一个通用的“限制-释放”框架，用于计算构象变化的自由能。我们通过证明伞式采样协议可以获得与起始蛋白质结构无关的聚合结合自由能，并包括这些构象变化自由能，来说明它在该模型系统中的使用。
Free energy calculations are increasingly being used to estimate absolute and relative binding free energies of ligands to proteins. However, computed free energies often appear to depend on the initial protein conformation, indicating incomplete sampling. This is especially true when proteins can change conformation on ligand binding, as free energies associated with these conformational changes are either ignored or assumed to be included by virtue of the sampling performed in the calculation. Here, we show that, in a model protein system (a designed binding site in T4 lysozyme), conformational changes can make a difference of several kcal/mol in computed binding free energies and that they are neglected in computed binding free energies if the system remains kinetically trapped in a particular metastable state on simulation timescales. We introduce a general "confine-and-release" framework for free energy calculations that accounts for these free energies of conformational change. We illustrate its use in this model system by demonstrating that an umbrella sampling protocol can obtain converged binding free energies that are independent of the starting protein structure and include these conformational change free energies.