Wang Ting, Wade Rebecca C
Molecular and Cellular Modeling Group, EML Research, Schloss-Wolfsbrunnenweg 33, 69118 Heidelberg, Germany.
J Chem Theory Comput. 2006 Jan;2(1):140-8. doi: 10.1021/ct0501607.
The secondary structure propensities observed in protein simulations depend heavily on the force field parameters used. The existing empirical force fields often have difficulty in balancing the relative stabilities of helical and extended conformations. The resultant secondary structure bias may not be apparent in short simulations at room temperature starting from the native folded states. However, it can manifest itself dramatically at high temperatures and lead to large deviations from experimentally observed secondary structure propensities. Motivated by thermal unfolding simulations of several WW domains, which have a three-stranded β-sheet structure, we chose the FBP28 WW domain as a well-characterized system to investigate several AMBER force fields as well as parametrization of the NPSA (Neutralized, Polarized ionizable side chains with a solvent-accessible Surface Area-dependent term) implicit solvent model. The ff94 force field and two variants with altered parameters for the backbone torsion term were found to convert the native β-sheet structure directly to a single helix at high temperatures, whereas the ff96 force field produced significant non-native β-sheet content at high temperatures. The ff03 force field was able to reproduce the β-sheet-coil transition and experimentally observed unfolding pathways with both an explicit water solvent and the NPSA implicit solvent model at relatively low temperatures. However, the protein domain became predominantly helical after unfolding. Modification of the solvation parameter in the NPSA implicit solvent model was not sufficient to remedy this problem. The results imply that the intrinsic secondary structure bias in a force field cannot easily be solved by modifying a single parameter such as backbone torsion potential or a solvation parameter of a solvent model. Nevertheless, the results show that the AMBER ff03 force field together with an explicit solvent model or the NPSA implicit solvent model is a useful tool for studying the unfolding of both α- and β-sheet structure protein domains, and an integrative consideration of all force field parameters is likely to be necessary for a complete solution.
在蛋白质模拟中观察到的二级结构倾向在很大程度上取决于所使用的力场参数。现有的经验力场在平衡螺旋构象和伸展构象的相对稳定性方面常常存在困难。在从天然折叠态开始的室温短模拟中，由此产生的二级结构偏差可能并不明显。然而，在高温下它会显著表现出来，并导致与实验观察到的二级结构倾向有很大偏差。受几个具有三链β-折叠结构的WW结构域的热展开模拟的启发，我们选择FBP28 WW结构域作为一个特征明确的系统，来研究几种AMBER力场以及NPSA（具有与溶剂可及表面积相关项的中和、极化可电离侧链）隐式溶剂模型的参数化。发现ff94力场和两个对主链扭转项参数进行了改变的变体在高温下会将天然β-折叠结构直接转变为单螺旋，而ff96力场在高温下会产生大量非天然的β-折叠含量。ff03力场在相对较低温度下使用显式水溶剂和NPSA隐式溶剂模型时，能够重现β-折叠-卷曲转变以及实验观察到的展开途径。然而，蛋白质结构域在展开后主要变为螺旋结构。在NPSA隐式溶剂模型中对溶剂化参数的修改不足以解决这个问题。结果表明，力场中固有的二级结构偏差不能通过修改单个参数（如主链扭转势或溶剂模型的溶剂化参数）轻易解决。尽管如此，结果表明AMBER ff03力场与显式溶剂模型或NPSA隐式溶剂模型一起是研究α-和β-折叠结构蛋白质结构域展开的有用工具，并且对于完整的解决方案可能需要综合考虑所有力场参数。
