Guenot J, Kollman P A
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143.
Protein Sci. 1992 Sep;1(9):1185-205. doi: 10.1002/pro.5560010912.
Although aqueous simulations with periodic boundary conditions more accurately describe protein dynamics than in vacuo simulations, these are computationally intensive for most proteins. Trp repressor dynamic simulations with a small water shell surrounding the starting model yield protein trajectories that are markedly improved over gas phase, yet computationally efficient. Explicit water in molecular dynamics simulations maintains surface exposure of protein hydrophilic atoms and burial of hydrophobic atoms by opposing the otherwise asymmetric protein-protein forces. This properly orients protein surface side chains, reduces protein fluctuations, and lowers the overall root mean square deviation from the crystal structure. For simulations with crystallographic waters only, a linear or sigmoidal distance-dependent dielectric yields a much better trajectory than does a constant dielectric model. As more water is added to the starting model, the differences between using distance-dependent and constant dielectric models becomes smaller, although the linear distance-dependent dielectric yields an average structure closer to the crystal structure than does a constant dielectric model. Multiplicative constants greater than one, for the linear distance-dependent dielectric simulations, produced trajectories that are progressively worse in describing trp repressor dynamics. Simulations of bovine pancreatic trypsin were used to ensure that the trp repressor results were not protein dependent and to explore the effect of the nonbonded cutoff on the distance-dependent and constant dielectric simulation models. The nonbonded cutoff markedly affected the constant but not distance-dependent dielectric bovine pancreatic trypsin inhibitor simulations. As with trp repressor, the distance-dependent dielectric model with a shell of water surrounding the protein produced a trajectory in better agreement with the crystal structure than a constant dielectric model, and the physical properties of the trajectory average structure, both with and without a nonbonded cutoff, were comparable.
尽管与真空模拟相比，具有周期性边界条件的水相模拟能更准确地描述蛋白质动力学，但对于大多数蛋白质而言，这些模拟在计算上非常耗时。围绕起始模型有一个小水壳的色氨酸阻遏蛋白动态模拟产生的蛋白质轨迹，与气相模拟相比有显著改善，且计算效率高。分子动力学模拟中的显式水通过对抗原本不对称的蛋白质-蛋白质作用力，维持了蛋白质亲水原子的表面暴露和疏水原子的埋藏。这能正确地定向蛋白质表面侧链，减少蛋白质波动，并降低与晶体结构的整体均方根偏差。对于仅含结晶水的模拟，线性或S形距离依赖介电常数产生的轨迹比恒定介电常数模型要好得多。随着向起始模型中添加更多的水，使用距离依赖和恒定介电常数模型之间的差异变得更小，尽管线性距离依赖介电常数产生的平均结构比恒定介电常数模型更接近晶体结构。对于线性距离依赖介电常数模拟，大于1的乘法常数产生的轨迹在描述色氨酸阻遏蛋白动力学方面逐渐变差。使用牛胰蛋白酶进行模拟，以确保色氨酸阻遏蛋白的结果不依赖于蛋白质，并探索非键截断对距离依赖和恒定介电常数模拟模型的影响。非键截断对恒定介电常数但不对距离依赖介电常数的牛胰蛋白酶抑制剂模拟有显著影响。与色氨酸阻遏蛋白一样，蛋白质周围有水壳的距离依赖介电常数模型产生的轨迹与晶体结构的一致性比恒定介电常数模型更好，并且无论有无非键截断，轨迹平均结构的物理性质都是可比的。
