Conformational Transitions and Convergence of Absolute Binding Free Energy Calculations.
Conformational Transitions and Convergence of Absolute Binding Free Energy Calculations.
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DOI：
10.1021/ct200684b
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发表时间：
2012-01-10
影响因子：
5.5
通讯作者：
Levy, Ronald M.
中科院分区：
文献类型：
--
作者：
Lapelosa, Mauro;Gallicchio, Emilio;Levy, Ronald M.
结合能分布分析方法 (BEDAM) 用于计算一系列配体与隐式溶剂化的 FK506 结合蛋白 (FKBP12) 的标准结合自由能。结合自由能估计与实验亲和力相当吻合。通过模拟识别的配合物的构象与晶体学数据非常一致，晶体学数据没有用于限制配体方向。 BEDAM 方法基于 λ 跳跃哈密顿并行复制交换 (HREM) 分子动力学构象采样、OPLS-AA/AGBNP2 有效势和多态自由能估计器 (MBAR)。实现收敛且准确的结果取决于计算的所有这些元素。结合自由能的收敛与关键中间态处的结合能分布的收敛水平有关，其中结合态和非结合态处于平衡，并且其中结合/非结合构象转变的速率是最大的。这一发现反映了在有序/无序转变的背景下的类似观察结果，例如在蛋白质折叠中。获得有关配体结合和解除结合的物理机制的见解。最大的 FK506 配体的收敛只有在施加严格的构象限制后才能实现，但这需要对复合物结构有准确的先验结构知识。研究发现，AGBNP2 分析模型低估了这些以松散堆积的蛋白质-配体结合界面为特征的系统中结合的疏水驱动力的大小。使用数值表面积模型对结合能进行重新评分可以纠正这一缺陷。这项研究说明了能量模型、构象空间探索和从结合自由能计算获得稳健估计所需的自由能估计器之间复杂的相互作用。
The Binding Energy Distribution Analysis Method (BEDAM) is employed to compute the standard binding free energies of a series of ligands to a FK506 binding protein (FKBP12) with implicit solvation. Binding free energy estimates are in reasonably good agreement with experimental affinities. The conformations of the complexes identified by the simulations are in good agreement with crystallographic data, which was not used to restrain ligand orientations. The BEDAM method is based on λ -hopping Hamiltonian parallel Replica Exchange (HREM) molecular dynamics conformational sampling, the OPLS-AA/AGBNP2 effective potential, and multi-state free energy estimators (MBAR). Achieving converged and accurate results depends on all of these elements of the calculation. Convergence of the binding free energy is tied to the level of convergence of binding energy distributions at critical intermediate states where bound and unbound states are at equilibrium, and where the rate of binding/unbinding conformational transitions is maximal. This finding mirrors similar observations in the context of order/disorder transitions as for example in protein folding. Insights concerning the physical mechanism of ligand binding and unbinding are obtained. Convergence for the largest FK506 ligand is achieved only after imposing strict conformational restraints, which however require accurate prior structural knowledge of the structure of the complex. The analytical AGBNP2 model is found to underestimate the magnitude of the hydrophobic driving force towards binding in these systems characterized by loosely packed protein-ligand binding interfaces. Rescoring of the binding energies using a numerical surface area model corrects this deficiency. This study illustrates the complex interplay between energy models, exploration of conformational space, and free energy estimators needed to obtain robust estimates from binding free energy calculations.
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影响因子：
3.3
作者：
Bizzarri, Marco;Marsili, Simone;Procacci, Piero
通讯作者：
Procacci, Piero
影响因子：
15
作者：
Colizzi, Francesco;Perozzo, Remo;Cavalli, Andrea
通讯作者：
Cavalli, Andrea
DOI：
10.1021/jp807701h
发表时间：
2009-02-26
期刊：
The journal of physical chemistry. B
影响因子：
--
作者：
Deng Y;Roux B
通讯作者：
Roux B
影响因子：
13.8
作者：
Csermely, Peter;Palotai, Robin;Nussinov, Ruth
通讯作者：
Nussinov, Ruth
影响因子：
6.8
作者：
Guvench, Olgun;MacKerell, Alexander D., Jr.
通讯作者：
MacKerell, Alexander D., Jr.