Department of Theoretical Chemistry, Lund University, Chemical Centre, SE-221 00 Lund, Sweden.
J Comput Chem. 2011 Jan 30;32(2):187-95. doi: 10.1002/jcc.21546.
We study how the results of molecular dynamics (MD) simulations are affected by various choices during the setup, e.g., the starting velocities, the solvation, the location of protons, the conformation of His, Asn, and Gln residues, the protonation and titration of His residues, and the treatment of alternative conformations. We estimate the binding affinity of ligands to four proteins calculated with the MM/GBSA method (molecular mechanics combined with a generalized Born and surface area solvation energy). For avidin and T4 lysozyme, all variations gave similar results within 2 kJ/mol. For factor Xa, differences in the solvation or in the selection of alternative conformations gave results that are significantly different from those of the other approaches by 4-6 kJ/mol, whereas for galectin-3, changes in the conformations, rotations, and protonation gave results that differed by 10 kJ/mol, but only if residues close to the binding site were modified. This shows that the results of MM/GBSA calculations are reasonably reproducible even if the MD simulations are set up with different software. Moreover, we show that the sampling of phase space can be enhanced by solvating the systems with different equilibrated water boxes, in addition to the common use of different starting velocities. If different conformations are available in the crystal structure, they should also be employed to enhance the sampling. Protonation, ionization, and conformations of Asn, Gln, and His may also be used to enhance sampling, but great effort should be spent to obtain as reliable predictions as possible close to the active site.
我们研究了在设置过程中（例如起始速度、溶剂化、质子位置、His、Asn 和 Gln 残基的构象、His 残基的质子化和滴定以及替代构象的处理）分子动力学（MD）模拟的结果如何受到各种选择的影响。我们使用 MM/GBSA 方法（分子力学与广义 Born 和表面面积溶剂化能相结合）计算了四个蛋白质配体的结合亲和力。对于亲和素和 T4 溶菌酶，所有变体在 2 kJ/mol 内给出了相似的结果。对于因子 Xa，溶剂化或替代构象的选择差异导致的结果与其他方法相差 4-6 kJ/mol，而对于半乳糖凝集素-3，构象、旋转和质子化的变化导致的结果相差 10 kJ/mol，但仅当接近结合位点的残基发生改变时才会如此。这表明即使使用不同的软件设置 MD 模拟，MM/GBSA 计算的结果也具有相当的可重现性。此外，我们还表明，通过用不同的平衡水盒对系统进行溶剂化，可以增强相空间的采样，除了常用的不同起始速度之外。如果晶体结构中存在不同的构象，也应该使用它们来增强采样。质子化、离子化以及 Asn、Gln 和 His 的构象也可以用于增强采样，但应该花费大量精力尽可能靠近活性位点获得尽可能可靠的预测。
