Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece.
Biophys J. 2011 Oct 5;101(7):1766-71. doi: 10.1016/j.bpj.2011.08.044.
Slowly but steadily bibliographic evidence is accumulating that the apparent convergence of the various biomolecular force fields as evidenced from simulations of proteins in the folded state does not hold true for folding simulations. Here we add one more example to the growing list of peptides and proteins for which different force fields show irreconcilable differences in their folding predictions, even at such a fundamental level as that of a peptide's secondary structure. We show that for an undecamer peptide that is known from two independent NMR structure determinations to have a mainly 3(10)-helical structure in solution, three mainstream biomolecular force fields give completely disparate predictions: The CHARMM force field (with the CMAP correction) predicts an outstandingly stable α-helical structure, in disagreement not only with the experimental structures, but also with experimental evidence obtained from circular dichroism. OPLS-AA shows an almost totally disordered peptide with the most frequently observed folded conformation corresponding to a β-hairpin-like structure, again in disagreement with all available experimental evidence. Only the AMBER99SB force field appears to qualitatively agree with not only the general structural characteristics of the peptide (on the account of both NMR- and CD-based experiments), but to also correctly predict some of the experimentally observed interactions at the level of side chains. Possible interpretations of these findings are discussed.
缓慢但稳步地积累文献证据表明，在折叠模拟中，蛋白质折叠状态模拟中各种生物分子力场的明显收敛并不成立。在这里，我们将更多的肽和蛋白质添加到不断增长的列表中，这些肽和蛋白质的不同力场在折叠预测方面表现出不可调和的差异，甚至在肽的二级结构等基本水平上也是如此。我们表明，对于一种已知在溶液中具有主要 3(10)-螺旋结构的十一肽，三种主流生物分子力场给出了完全不同的预测：CHARMM 力场（带有 CMAP 修正）预测了一种非常稳定的α-螺旋结构，不仅与实验结构不一致，而且与从圆二色性获得的实验证据也不一致。OPLS-AA 显示出几乎完全无序的肽，最常观察到的折叠构象对应于β-发夹样结构，再次与所有可用的实验证据不一致。只有 AMBER99SB 力场似乎在定性上不仅与肽的一般结构特征（基于 NMR 和 CD 实验）一致，而且还正确预测了一些在侧链水平上观察到的实验相互作用。讨论了对这些发现的可能解释。
