Hierarchical Folding Free Energy Landscape of HP35 Revealed by Most Probable Path Clustering
Hierarchical Folding Free Energy Landscape of HP35 Revealed by Most Probable Path Clustering
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DOI：
10.1021/jp410398a
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发表时间：
2014-07-17
影响因子：
3.3
通讯作者：
Stock, Gerhard
中科院分区：
文献类型：
--
作者：
Jain, Abhinav;Stock, Gerhard
采用Shaw等人对绒毛蛋白头段蛋白（HP 35）进行的分子动力学模拟，对HP 35的折叠过程进行了详细的理论分析。该方法是基于最近提出的最可能路径算法，该算法确定了系统的亚稳态，结合这些状态的动态核，以获得一致的马尔可夫状态模型。该方法有助于构建与HP 35的折叠自由能景观相关的树状结构，揭示了分层漏斗结构，并表明原生状态是动力学陷阱而不是网络中心。HP 35的能量景观由熵展开的盆地U组成，在那里发生蛋白质的预结构化，中间盆地1，其通过反映螺旋-1的形成的限速U -> I过渡态连接到U，以及天然盆地N，其包含接近NMR结构的状态和表现出增强的螺旋-3波动的天然状态。该模型与最近的实验观察结果一致，即中间态和原生态的动力学差异最大（锁定态与解锁态）。采用二面角主成分分析，亚扩散运动的多维自由能表面。
Adopting extensive molecular dynamics simulations of villin headpiece protein (HP35) by Shaw and co-workers, a detailed theoretical analysis of the folding of HP35 is presented. The approach is based on the recently proposed most probable path algorithm which identifies the metastable states of the system, combined with dynamical coring of these states in order to obtain a consistent Markov state model. The method facilitates the construction of a dendrograrn associated with the folding free-energy landscape of HP35, which reveals a hierarchical funnel structure and shows that the native state is rather a kinetic trap than a network hub. The energy landscape of HP35 consists of the entropic unfolded basin U, where the prestructuring of the protein takes place, the intermediate basin 1, which is connected to U via the rate-limiting U -> I transition state reflecting the formation of helix-1, and the native basin N, containing a state close to the NMR structure and a native-like state that exhibits enhanced fluctuations of helix-3. The model is in line with recent experimental observations that the intermediate and native states differ mostly in their dynamics (locked vs unlocked states). Employing dihedral angle principal component analysis, subdiffusive motion on a multidimensional free-energy surface is found.