Multiscale Monte Carlo Sampling of Protein Sidechains: Application to Binding Pocket Flexibility.
Multiscale Monte Carlo Sampling of Protein Sidechains: Application to Binding Pocket Flexibility.
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DOI：
10.1021/ct700334a
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发表时间：
2008-05
影响因子：
5.5
通讯作者：
Jerome P. Nilmeier;M. Jacobson
中科院分区：
文献类型：
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作者：
Jerome P. Nilmeier;M. Jacobson
我们提出了一个蒙特卡罗侧链抽样程序，并将其应用于评估蛋白质结合口袋的灵活性。我们实现了一个多“时间步长”的蒙特卡罗算法，以优化侧链采样与表面广义玻恩隐式溶剂模型。在这种方法中，某些力（由于长程静电和隐式溶剂模型）不经常更新，在“外步骤”，而短程力（共价，局部非键相互作用）在每个“内步骤”更新。研究了两个多步骤方案。第一个协议严格遵守详细的平衡，第二个协议引入了近似的溶剂化项，增加了接受率。第一个协议比不使用多个时间步长的协议提高了10倍，而第二个协议生成了相当的集合，并提高了15倍。发现每个外部步骤50-200个内部步骤的范围对于两个协议都给出最佳性能。所得方法是评估配体结合口袋中侧链灵活性的实用手段，正如我们对六种蛋白质的原理验证计算所示：DB 3抗体，嗜热菌蛋白酶，雌激素受体，PPAR-γ，PI 3激酶和CDK 2。所得的载脂蛋白结合位点的侧链集合与已知的诱导的拟合构象变化很好地相关，并提供了对结合口袋灵活性的见解。
We present a Monte Carlo sidechain sampling procedure and apply it to assessing the flexibility of protein binding pockets. We implemented a multiple "time step" Monte Carlo algorithm to optimize sidechain sampling with a surface generalized Born implicit solvent model. In this approach, certain forces (those due to long-range electrostatics and the implicit solvent model) are updated infrequently, in "outer steps", while short-range forces (covalent, local nonbonded interactions) are updated at every "inner step". Two multistep protocols were studied. The first protocol rigorously obeys detailed balance, and the second protocol introduces an approximation to the solvation term that increases the acceptance ratio. The first protocol gives a 10-fold improvement over a protocol that does not use multiple time steps, while the second protocol generates comparable ensembles and gives a 15-fold improvement. A range of 50-200 inner steps per outer step was found to give optimal performance for both protocols. The resultant method is a practical means to assess sidechain flexibility in ligand binding pockets, as we illustrate with proof-of-principle calculations on six proteins: DB3 antibody, thermolysin, estrogen receptor, PPAR-γ, PI3 kinase, and CDK2. The resulting sidechain ensembles of the apo binding sites correlate well with known induced fit conformational changes and provide insights into binding pocket flexibility.