Department of Chemistry, Biochemistry, and Institute of Biomedical Studies, Baylor University, Waco, Texas 76706, USA.
J Phys Chem A. 2010 Dec 2;114(47):12391-402. doi: 10.1021/jp102612d. Epub 2010 Nov 8.
We used a combined approach of experiment and simulation to determine the helical population and folding pathway of a small helix forming blocked pentapeptide, Ac-(Ala)(5)-NH(2). Experimental structural characterization of this blocked peptide was carried out with far UV circular dichroism spectroscopy, FTIR, and NMR measurements. These measurements confirm the presence of the α-helical state in a buffer solution. Direct molecular dynamics and replica-exchange simulations of the pentapeptide were performed using several popular force fields with explicit solvent. The simulations yielded statistically reliable estimates of helix populations, melting curves, folding, and nucleation times. The distributions of conformer populations are used to measure folding cooperativity. Finally, a statistical analysis of the sample of helix-coil transition paths was performed. The details of the calculated helix populations, folding kinetics and pathways vary with the employed force field. Interestingly, the helix populations, folding, and unfolding times obtained from most of the studied force fields are in qualitative agreement with each other and with available experimental data, with the deviations corresponding to several kcal/mol in energy at 300 K. Most of the force fields also predict qualitatively similar transition paths, with unfolding initiated at the C-terminus. Accuracy of potential energy parameters, rather than conformational sampling may be the limiting factor in current molecular simulations.
我们采用实验和模拟相结合的方法来确定一个小的螺旋形成的封闭五肽，Ac-(Ala)(5)-NH(2)的螺旋种群和折叠途径。通过远紫外圆二色光谱、FTIR 和 NMR 测量对该封闭肽进行了实验结构表征。这些测量证实了在缓冲溶液中存在α-螺旋状态。使用几种流行的含溶剂的力场对五肽进行了直接分子动力学和复制交换模拟。模拟产生了螺旋种群、熔融曲线、折叠和成核时间的统计可靠估计。构象种群分布用于测量折叠协同性。最后，对螺旋-卷曲转变路径的样本进行了统计分析。计算得到的螺旋种群、折叠动力学和途径的细节随所使用的力场而变化。有趣的是，从大多数研究的力场中获得的螺旋种群、折叠和展开时间与彼此以及可用的实验数据定性一致，偏差对应于 300 K 时能量的几个千卡摩尔。大多数力场还预测了具有相似折叠途径的解折叠，从 C 端开始。在当前的分子模拟中，可能限制因素是势能参数的准确性，而不是构象采样。
