Simulating protein folding initiation sites using an alpha-carbon-only knowledge-based force field.
Simulating protein folding initiation sites using an alpha-carbon-only knowledge-based force field.
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DOI：
10.1002/prot.22348
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发表时间：
2009-08-01
期刊：
影响因子：
2.9
通讯作者：
Bystroff C
中科院分区：
文献类型：
--
作者：
Buck PM;Bystroff C
蛋白质折叠是一个分层的过程，首先在局部形成结构，然后在全局形成结构。一些短的序列片段通过强的结构偏好启动折叠，这与它们在蛋白质中的三维背景无关。我们已经构建了一个基于知识的力场，其中的能量函数是有条件的局部序列模式，表示在隐马尔可夫模型的局部结构（HMMSTR）。碳-α力场（CALF）基于α-碳虚拟键打开和二面角、成对接触和氢键供体-受体对的数据库频率构建序列特异性统计势，并通过布朗动力学模拟折叠。我们引入氢键供体和受体势作为α-碳概率场，其条件是预测的局部序列。恒温模拟进行了选择27肽作为假定的折叠起始位点，每个12个残基的长度，代表几个不同的局部结构基序。每个0.6 μs轨迹基于结构聚类。通过细分轨迹和比较聚类来评估模拟收敛性或代表性。对于27个序列中的21个，最大的集群占总轨迹的一半以上。在这21个序列中，有14个序列的聚类中心与相应全长蛋白质中的天然结构最多相差2.6均方根偏差（RMSD）。为了评估能量函数对非局部相互作用的充分性，使用布朗动力学模拟放松了11个全长天然结构。平衡结构偏离了它们的自然状态，但保持了它们的整体拓扑结构和紧凑性。一个简单的潜力，折叠蛋白质的局部和稳定的蛋白质的全球可能使一个更现实的理解分层折叠途径。
Protein folding is a hierarchical process where structure forms locally first, then globally. Some short sequence segments initiate folding through strong structural preferences that are independent of their three-dimensional context in proteins. We have constructed a knowledge-based force field in which the energy functions are conditional on local sequence patterns, as expressed in the hidden Markov model for local structure (HMMSTR). Carbon-alpha force field (CALF) builds sequence specific statistical potentials based on database frequencies for α-carbon virtual bond opening and dihedral angles, pairwise contacts and hydrogen bond donor-acceptor pairs, and simulates folding via Brownian dynamics. We introduce hydrogen bond donor and acceptor potentials as α-carbon probability fields that are conditional on the predicted local sequence. Constant temperature simulations were carried out using 27 peptides selected as putative folding initiation sites, each 12 residues in length, representing several different local structure motifs. Each 0.6 μs trajectory was clustered based on structure. Simulation convergence or representativeness was assessed by subdividing trajectories and comparing clusters. For 21 of the 27 sequences, the largest cluster made up more than half of the total trajectory. Of these 21 sequences, 14 had cluster centers that were at most 2.6 Å root mean square deviation (RMSD) from their native structure in the corresponding full-length protein. To assess the adequacy of the energy function on nonlocal interactions, 11 full length native structures were relaxed using Brownian dynamics simulations. Equilibrated structures deviated from their native states but retained their overall topology and compactness. A simple potential that folds proteins locally and stabilizes proteins globally may enable a more realistic understanding of hierarchical folding pathways.