Lin Zhixiong, Van Gunsteren Wilfred F, Liu Haiyan
School of Life Sciences and Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China (USTC), Hefei, Anhui 230027, People's Republic of China; Laboratory of Physical Chemistry, Swiss Federal Institute of Technology, ETH, 8093 Zurich, Switzerland.
J Comput Chem. 2011 Jul 30;32(10):2290-7. doi: 10.1002/jcc.21818. Epub 2011 May 3.
The one-step free energy perturbation approach can be applied to obtain conformational state-specific free energy differences (FEDs) associated with changes in force field parameters, and thus offers the possibility to consider conformational equilibria during force field parameterization. In this work, using the alanine decapeptide in explicit water solution as a model, the α-helical and β-hairpin state-specific FEDs associated with force field changes between two widely used parameter sets of the GROMOS force field, namely, 43A1 and 53A6, were determined using one-step perturbation. The results mostly deviated by only 1 kJ mol(−1) in absolute or a few percent in relative values from thermodynamic integration results, suggesting that the convergence ranges of one-step perturbation were large enough to cover the substantial changes in nonbonded parameters between the two parameter sets. It was also found that one-step perturbation may give larger errors when the changes from the reference state include a large decrease in van der Waals radius, as indicated by the result for the β-hairpin state-specific free energy change going from 53A6 to 43A1. According to the free energy results, the α-helical state of the alanine decapeptide is destabilized by 15 kJ mol(−1), i.e., 1.5 kJ mol(−1) per residue, relative to the β-hairpin state when going from 43A1 to 53A6, in agreement with previous direct simulations in which native α-helices were often found to be unstable in simulations using 53A6, despite that the 53A6 parameters better reproduce a range of thermodynamic properties of small molecular systems. By applying one-step perturbation to analyze the effects of perturbing individual parameters, the differential stabilization of the two secondary structure states can be traced to the changes in van der Waals parameters, especially a van der Waals parameter involved in third-neighbor interactions. This study provides an example of the efficiency of one-step perturbation in force field development, reducing the computational cost by orders of magnitude.
一步自由能微扰方法可用于获得与力场参数变化相关的构象状态特异性自由能差（FED），从而为在力场参数化过程中考虑构象平衡提供了可能性。在这项工作中，以在明确水溶液中的丙氨酸十肽为模型，使用一步微扰法确定了与GROMOS力场的两个广泛使用的参数集（即43A1和53A6）之间的力场变化相关的α-螺旋和β-发夹状态特异性FED。结果与热力学积分结果相比，绝对值大多仅相差1 kJ mol⁻¹，相对值相差百分之几，这表明一步微扰的收敛范围足够大，能够涵盖两个参数集之间非键参数的实质性变化。还发现，当从参考状态的变化包括范德华半径大幅减小时，一步微扰可能会产生较大误差，从53A6到43A1的β-发夹状态特异性自由能变化结果表明了这一点。根据自由能结果，当从43A1变为53A6时，丙氨酸十肽的α-螺旋状态相对于β-发夹状态不稳定15 kJ mol⁻¹，即每个残基不稳定1.5 kJ mol⁻¹，这与之前的直接模拟结果一致，在使用53A6的模拟中，尽管53A6参数能更好地重现小分子系统的一系列热力学性质，但天然α-螺旋通常被发现是不稳定的。通过应用一步微扰来分析单个参数微扰的影响，两种二级结构状态的差异稳定性可以追溯到范德华参数的变化，特别是涉及第三近邻相互作用的范德华参数。这项研究提供了一个一步微扰在力场开发中效率的例子，将计算成本降低了几个数量级。
