Laboratory of Physical Chemistry, Swiss Federal Institute of Technology, ETH 8093, Zurich, Switzerland.
J Comput Chem. 2010 Oct;31(13):2419-27. doi: 10.1002/jcc.21534.
Computer simulation using molecular dynamics is increasingly used to simulate the folding equilibria of peptides and small proteins. Yet, the quality of the obtained results depends largely on the quality of the force field used. This comprises the solute as well as the solvent model and their energetic and entropic compatibility. It is, however, computational very expensive to perform test simulations for each combination of force-field parameters. Here, we use the one-step perturbation technique to predict the change of the free enthalpy of folding of a beta-peptide in methanol solution due to changing a variety of force-field parameters. The results show that changing the solute backbone partial charges affects the folding equilibrium, whereas this is relatively insensitive to changes in the force constants of the torsional energy terms of the force field. Extending the cut-off distance for nonbonded interactions beyond 1.4 nm does not affect the folding equilibrium. The same result is found for a change of the reaction-field permittivity for methanol from 17.7 to 30. The results are not sensitive to the criterion, e.g., atom-positional RMSD or number of hydrogen bonds, that is used to distinguish folded and unfolded conformations. Control simulations with perturbed Hamiltonians followed by backward one-step perturbation indicated that quite large perturbations still yield reliable results. Yet, perturbing all solvent molecules showed where the limitations of the one-step perturbation technique are met. The evaluated methodology constitutes an efficient tool in force-field development for molecular simulation by reducing the number of required separate simulations by orders of magnitude.
使用分子动力学进行计算机模拟越来越多地被用于模拟肽和小蛋白的折叠平衡。然而，获得的结果的质量在很大程度上取决于所使用的力场的质量。这包括溶质和溶剂模型及其能量和熵的兼容性。然而，对于每种力场参数组合执行测试模拟在计算上非常昂贵。在这里，我们使用一步扰动技术来预测由于改变各种力场参数而导致甲醇溶液中β-肽的折叠自由焓的变化。结果表明，改变溶质骨架部分电荷会影响折叠平衡，而这对于力场扭转能量项的力常数的变化相对不敏感。将非键相互作用的截止距离扩展到 1.4nm 以上不会影响折叠平衡。对于甲醇的反应场介电常数从 17.7 到 30 的变化，也会得到相同的结果。结果对于用于区分折叠和未折叠构象的标准（例如，原子位置 RMSD 或氢键的数量）不敏感。用扰动哈密顿量进行的控制模拟，然后进行后向一步扰动表明，相当大的扰动仍然可以得到可靠的结果。然而，扰动所有溶剂分子显示了一步扰动技术的局限性所在。评估的方法构成了通过数量级减少所需的单独模拟的数量，用于分子模拟的力场开发的有效工具。
