State Key Laboratory of Precision Spectroscopy and Department of Physics, Institute of Theoretical and Computational Science, East China Normal University, Shanghai, China.
J Phys Chem B. 2012 Jan 12;116(1):549-54. doi: 10.1021/jp208953x. Epub 2011 Dec 12.
Simulation result for protein folding/unfolding is highly dependent on the accuracy of the force field employed. Even for the simplest structure of protein such as a short helix, simulations using the existing force fields often fail to produce the correct structural/thermodynamic properties of the protein. Recent research indicated that lack of polarization is at least partially responsible for the failure to successfully fold a short helix. In this work, we develop a simple formula-based atomic charge polarization model for intraprotein (backbone) hydrogen bonding based on the existing AMBER force field to study the thermal stability of a short helix (2I9M) by replica exchange molecular dynamics simulation. By comparison of the simulation results with those obtained by employing the standard AMBER03 force field, the formula-based atomic charge polarization model gave the helix melting curve in close agreement with the NMR experiment. However, in simulations using the standard AMBER force field, the helix was thermally unstable at the temperature of the NMR experiment, with a melting temperature almost below the freezing point. The difference in observed thermal stability from these two simulations is the effect of backbone intraprotein polarization, which was included in the formula-based atomic charge polarization model. The polarization of backbone hydrogen bonding thus plays a critical role in the thermal stability of helix or more general protein structures.
蛋白质折叠/展开的模拟结果高度依赖于所使用力场的准确性。即使对于蛋白质的最简单结构，如短螺旋，使用现有力场的模拟也常常无法产生蛋白质的正确结构/热力学性质。最近的研究表明，缺乏极化至少部分是导致短螺旋无法成功折叠的原因。在这项工作中，我们根据现有的 AMBER 力场，为蛋白质内（骨架）氢键开发了一种简单的基于公式的原子电荷极化模型，通过 replica exchange 分子动力学模拟研究短螺旋（2I9M）的热稳定性。通过将模拟结果与使用标准 AMBER03 力场获得的结果进行比较，基于公式的原子电荷极化模型给出的螺旋熔化曲线与 NMR 实验非常吻合。然而，在使用标准 AMBER 力场的模拟中，螺旋在 NMR 实验的温度下热不稳定，其熔化温度几乎低于冰点。这两种模拟中观察到的热稳定性差异是骨架内蛋白质极化的影响，该影响包含在基于公式的原子电荷极化模型中。因此，骨架氢键的极化在螺旋或更一般的蛋白质结构的热稳定性中起着关键作用。
