Cavalli Andrea, Ferrara Philippe, Caflisch Amedeo
Department of Biochemistry, University of Zurich, Zurich, Switzerland.
Proteins. 2002 May 15;47(3):305-14. doi: 10.1002/prot.10041.
The thermodynamics and energetics of a 20-residue synthetic peptide with a stable three-stranded antiparallel beta-sheet fold are investigated by implicit solvent molecular dynamics (MD) at 330 K (slightly above the melting temperature in the model) and compared with previous simulation results at 360 K. At both temperature values, the peptide folds reversibly to the NMR solution conformation, irrespective of the starting conformation. The sampling of the conformational space (2.3 micros and 25 folding events at 330 K, and 3 micros and 50 folding events at 360 K) is sufficient to obtain a thermodynamic description of minima and transition states on the free energy surface, which is determined near equilibrium by counting populations. The free energy surface, plotted as a function of two-order parameters that monitor formation of either of the beta-hairpins, is similar at both temperature values. The statistically predominant folding pathway and its frequency (about two-thirds of the folding events) are the same at 330 K and 360 K. Furthermore, the main unfolding route is the reverse of the predominant folding pathway. The effective energy and its electrostatic and van der Waals contributions show a downhill profile at both temperatures, implying that the free energy barrier is of entropic origin and corresponds to the freezing of about two-thirds of the chain into a beta-hairpin conformation. The average folding rate is nearly the same at 330 K and 360 K, while the unfolding rate is about four times slower at 330 K than at 360 K. Taken together with previous MD analysis of alpha-helices and beta-hairpins, the present simulation results indicate that the free energy surface and folding mechanism of structured peptides have a weak temperature dependence.
通过在330 K（略高于模型中的熔解温度）下的隐式溶剂分子动力学（MD）研究了具有稳定三链反平行β-折叠结构的20残基合成肽的热力学和能量学，并与之前在360 K下的模拟结果进行了比较。在这两个温度值下，无论起始构象如何，该肽都能可逆地折叠成NMR溶液构象。构象空间的采样（330 K下为2.3微秒和25次折叠事件，360 K下为3微秒和50次折叠事件）足以获得自由能表面上最小值和过渡态的热力学描述，通过计算群体在接近平衡时确定。以监测任一β-发夹形成的两个序参量为函数绘制的自由能表面在两个温度值下相似。在330 K和360 K下，统计学上占主导的折叠途径及其频率（约三分之二的折叠事件）相同。此外，主要的解折叠途径与占主导的折叠途径相反。有效能量及其静电和范德华贡献在两个温度下均呈现下降趋势，这意味着自由能垒起源于熵，对应于约三分之二的链冻结成β-发夹构象。330 K和360 K下的平均折叠速率几乎相同，而330 K下的解折叠速率比360 K下慢约四倍。结合之前对α-螺旋和β-发夹的MD分析，目前的模拟结果表明，结构化肽的自由能表面和折叠机制对温度的依赖性较弱。
