Demchuk E, Bashford D, Case D A
Department of Molecular Biology, Scripps Research Institute, La Jolla, CA 92037, USA.
Fold Des. 1997;2(1):35-46. doi: 10.1016/S1359-0278(97)00004-7.
Peptide sequences with aromatic groups flanking a cis-proline residue are known to have a high propensity for adopting compact structures in which the aromatic sidechains pack against the proline ring. In particular, the sequence Ser-Tyr-Pro-Phe-Asp-Val (and variants of this) is known by NMR to form a high proportion of type VI turns in aqueous solution. We set out to explore the energetic and dynamic features of such sequences using molecular dynamics simulation techniques.
The conformation properties of the linear pentapeptide NH3(+)-Ala-Tyr-cisPro-Tyr-Asp-NMA (cis-AYPYD) have been explored in three solvated molecular dynamics simulations. The first began from an NMR-derived model structure containing a type VIa turn and close-stacking interactions between the tyrosine and proline sidechains. During 20 ns of simulation, the peptide made transitions between type VIa and VIb turns, but did not 'unfold' to more extended conformers, consistent with the unusual stability for folded forms observed by NMR for this sequence. Distances monitored by nuclear Overhauser peaks and sidechain rotamer populations in the trajectory are in good agreement with NMR data. Two additional 5 ns trajectories were begun from more extended conformers. The first folded into a conformer much like the NMR-derived structure within 3 ns and remained folded for the remainder of the trajectory. The second was begun from a structure in which the sidechain orientations were deliberately misfolded relative to that required for turn formation; this structure did not make a transition to a turn-like state.
The kinetic stability of folded forms of AYPYD, along with the observation of spontaneous folding from an extended conformation, indicates that the special stability seen experimentally is reflected in computer simulations. The results provide new information about the stabilization of secondary structure in short peptides, particularly by aromatic-proline interactions, and offer a description of pathways of interconversion of type VIa and VIb turns.
已知在顺式脯氨酸残基两侧带有芳香基团的肽序列具有形成紧密结构的高度倾向，其中芳香族侧链堆积在脯氨酸环上。特别是，序列Ser-Tyr-Pro-Phe-Asp-Val（及其变体）通过核磁共振（NMR）已知在水溶液中形成高比例的VI型转角。我们着手使用分子动力学模拟技术探索此类序列的能量和动力学特征。
在三个溶剂化分子动力学模拟中研究了线性五肽NH3(+)-Ala-Tyr-cisPro-Tyr-Asp-NMA（顺式-AYPYD）的构象性质。第一个模拟从一个包含VIa型转角以及酪氨酸和脯氨酸侧链之间紧密堆积相互作用的NMR衍生模型结构开始。在20纳秒的模拟过程中，该肽在VIa型和VIb型转角之间转变，但没有“展开”成更伸展的构象，这与NMR观察到的该序列折叠形式的异常稳定性一致。轨迹中通过核Overhauser峰监测的距离和侧链旋转异构体群体与NMR数据高度吻合。另外两个5纳秒的轨迹从更伸展的构象开始。第一个在3纳秒内折叠成一个与NMR衍生结构非常相似的构象，并在轨迹的其余部分保持折叠状态。第二个从一个侧链取向相对于形成转角所需的取向故意错误折叠的结构开始；该结构没有转变为类似转角的状态。
AYPYD折叠形式的动力学稳定性，以及从伸展构象自发折叠的观察结果，表明实验中观察到的特殊稳定性在计算机模拟中得到了体现。这些结果提供了关于短肽二级结构稳定化的新信息，特别是通过芳香族-脯氨酸相互作用，并描述了VIa型和VIb型转角相互转化的途径。
