Krivov Sergei V, Karplus Martin
Laboratoire de Chimie Biophysique, Institut de Science et d'Ingénierie Supramoléculaires, Université Louis Pasteur, 67000 Strasbourg, France.
Proc Natl Acad Sci U S A. 2004 Oct 12;101(41):14766-70. doi: 10.1073/pnas.0406234101. Epub 2004 Oct 4.
An understanding of the thermodynamics and kinetics of protein folding requires a knowledge of the free energy surface governing the motion of the polypeptide chain. Because of the many degrees of freedom involved, surfaces projected on only one or two progress variables are generally used in descriptions of the folding reaction. Such projections result in relatively smooth surfaces, but they could mask the complexity of the unprojected surface. Here we introduce an approach to determine the actual (unprojected) free energy surface and apply it to the second beta-hairpin of protein G, which has been used as a model system for protein folding. The surface is represented by a disconnectivity graph calculated from a long equilibrium folding-unfolding trajectory. The denatured state is found to have multiple low free energy basins. Nevertheless, the peptide shows exponential kinetics in folding to the native basin. Projected surfaces obtained from the present analysis have a simple form in agreement with other studies of the beta-hairpin. The hidden complexity found for the beta-hairpin surface suggests that the standard funnel picture of protein folding should be revisited.
要理解蛋白质折叠的热力学和动力学，需要了解控制多肽链运动的自由能表面。由于涉及许多自由度，在描述折叠反应时通常使用仅投影在一个或两个进展变量上的表面。这种投影会产生相对平滑的表面，但可能掩盖未投影表面的复杂性。在这里，我们介绍一种确定实际（未投影）自由能表面的方法，并将其应用于蛋白质G的第二个β-发夹结构，该结构已被用作蛋白质折叠的模型系统。该表面由从长平衡折叠-去折叠轨迹计算得到的不连通性图表示。发现变性态有多个低自由能盆地。然而，该肽在折叠到天然盆地时表现出指数动力学。从本分析中获得的投影表面具有与β-发夹结构的其他研究一致的简单形式。β-发夹结构表面发现的隐藏复杂性表明，应重新审视蛋白质折叠的标准漏斗图。
