On the use of orientational restraints and symmetry corrections in alchemical free energy calculations
On the use of orientational restraints and symmetry corrections in alchemical free energy calculations
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DOI：
10.1063/1.2221683
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发表时间：
2006-08-28
影响因子：
4.4
通讯作者：
Dill, Ken A.
中科院分区：
文献类型：
--
作者：
Mobley, David L.;Chodera, John D.;Dill, Ken A.
炼金术自由能计算正成为计算小分子配体与蛋白质的绝对结合自由能的有用工具。在这里，我们发现，存在多个亚稳配体取向时，单独使用距离限制会导致收敛问题。我们证明，使用方向的限制，可以大大加快这些计算的收敛。然而，即使有这样的加速，我们发现，足够的采样需要更长的模拟比在许多已公布的协议。为了进一步加速收敛，我们引入了一种新的方法，配置空间分解的方向，减少所需的模拟长度的至少一个因素的情况下检查。我们的方法是很容易并行化，非常适合的情况下，配体共晶结构是不可用的，并可以利用对接包产生的初始取向。(c)2006年，美国物理学会。
Alchemical free energy calculations are becoming a useful tool for calculating absolute binding free energies of small molecule ligands to proteins. Here, we find that the presence of multiple metastable ligand orientations can cause convergence problems when distance restraints alone are used. We demonstrate that the use of orientational restraints can greatly accelerate the convergence of these calculations. However, even with this acceleration, we find that sufficient sampling requires substantially longer simulations than are used in many published protocols. To further accelerate convergence, we introduce a new method of configuration space decomposition by orientation which reduces required simulation lengths by at least a factor of 5 in the cases examined. Our method is easily parallelizable, well suited for cases where a ligand cocrystal structure is not available, and can utilize initial orientations generated by docking packages. (c) 2006 American Institute of Physics.