Blinov N, Berjanskii M, Wishart D S, Stepanova M
National Institute for Nanotechnology NRC, Edmonton, Alberta T6G 2M9, Canada.
Biochemistry. 2009 Feb 24;48(7):1488-97. doi: 10.1021/bi802043h.
In this study we describe a novel approach to define structural domains and to characterize the local flexibility in both human and chicken prion proteins. The approach we use is based on a comprehensive theory of collective dynamics in proteins that was recently developed. This method determines the essential collective coordinates, which can be found from molecular dynamics trajectories via principal component analysis. Under this particular framework, we are able to identify the domains where atoms move coherently while at the same time to determine the local main-chain flexibility for each residue. We have verified this approach by comparing our results for the predicted dynamic domain systems with the computed main-chain flexibility profiles and the NMR-derived random coil indexes for human and chicken prion proteins. The three sets of data show excellent agreement. Additionally, we demonstrate that the dynamic domains calculated in this fashion provide a highly sensitive measure of protein collective structure and dynamics. Furthermore, such an analysis is capable of revealing structural and dynamic properties of proteins that are inaccessible to the conventional assessment of secondary structure. Using the collective dynamic simulation approach described here along with a high-temperature simulations of unfolding of human prion protein, we have explored whether locations of relatively low stability could be identified where the unfolding process could potentially be facilitated. According to our analysis, the locations of relatively low stability may be associated with the beta-sheet formed by strands S1 and S2 and the adjacent loops, whereas helix HC appears to be a relatively stable part of the protein. We suggest that this kind of structural analysis may provide a useful background for a more quantitative assessment of potential routes of spontaneous misfolding in prion proteins.
在本研究中，我们描述了一种全新的方法，用于定义人类和鸡朊病毒蛋白的结构域并表征其局部柔韧性。我们所采用的方法基于最近发展起来的蛋白质集体动力学综合理论。该方法可确定基本的集体坐标，通过主成分分析从分子动力学轨迹中找到这些坐标。在这个特定框架下，我们能够识别原子协同移动的结构域，同时确定每个残基的局部主链柔韧性。我们通过将预测的动态结构域系统结果与计算得到的主链柔韧性图谱以及人类和鸡朊病毒蛋白的核磁共振衍生随机卷曲指数进行比较，验证了这种方法。这三组数据显示出极佳的一致性。此外，我们证明以这种方式计算得到的动态结构域为蛋白质集体结构和动力学提供了一种高度灵敏的度量。而且，这样的分析能够揭示传统二级结构评估无法触及的蛋白质结构和动力学特性。利用这里描述的集体动态模拟方法以及人类朊病毒蛋白展开的高温模拟，我们探究了是否能够确定相对低稳定性的位置，在这些位置展开过程可能会得到促进。根据我们的分析，相对低稳定性的位置可能与由链S1和S2以及相邻环形成的β-折叠相关，而螺旋HC似乎是蛋白质中相对稳定的部分。我们认为这种结构分析可能为更定量地评估朊病毒蛋白自发错误折叠的潜在途径提供有用的背景。
