Folding processes of the B domain of protein A to the native state observed in all-atom ab initio folding simulations
Folding processes of the B domain of protein A to the native state observed in all-atom ab initio folding simulations
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DOI：
10.1063/1.2937135
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发表时间：
2008-06-21
影响因子：
4.4
通讯作者：
Duan, Yong
中科院分区：
文献类型：
--
作者：
Lei, Hongxing;Wu, Chun;Duan, Yong
达到天然状态的小蛋白质，一个必要的一步，全面了解折叠机制，仍然是一个巨大的挑战，从头开始蛋白质折叠模拟，尽管广泛的努力。本文采用AMBER FF 03全原子力场，对蛋白A的B结构域（BdpA）的折叠过程进行了常规分子动力学和复制交换分子动力学模拟。从一个扩展的链，共40个传统的（每到1.0 μ s）和两套副本交换（每到200.0 ns每个副本）的分子动力学模拟进行了不同的广义玻恩溶剂化模型和温度控制方案。力场和溶剂模型的改进允许成功模拟折叠过程到自然状态，如由最佳折叠结构的0.80埃C-alpha均方根偏差（RMSD）所证明的。最常见的构象是具有高种群的天然折叠结构。这是一个显着的改进，超过2.8埃的C-alpha RMSD的最佳天然结构从以前的从头折叠研究BdpA。据我们所知，我们的研究结果表明，第一次，从头模拟可以达到原生状态的BdpA。与实验观察结果一致，包括Phi值分析，螺旋II/III发夹的形成是一个关键步骤，它提供了一个模板，螺旋I可以形成，折叠过程可以完成。观察到螺旋III的早期形成，这与三种螺旋中分离的螺旋III的较高残余螺旋含量的实验结果一致。计算得到的温度分布和熔化温度与实验结果吻合较好。模拟进一步揭示了苯丙氨酸31可能对实现三个螺旋的正确包装起关键作用，这与实验观察一致。除了机理研究外，还基于物理能和统计势进行了从头计算结构预测。基于最低物理能量，预测的结构与实验确定的结构相差2.0埃C-alpha RMSD。(C)2008年美国物理学会。
Reaching the native states of small proteins, a necessary step towards a comprehensive understanding of the folding mechanisms, has remained a tremendous challenge to ab initio protein folding simulations despite the extensive effort. In this work, the folding process of the B domain of protein A (BdpA) has been simulated by both conventional and replica exchange molecular dynamics using AMBER FF03 all-atom force field. Started from an extended chain, a total of 40 conventional (each to 1.0 mu s) and two sets of replica exchange (each to 200.0 ns per replica) molecular dynamics simulations were performed with different generalized-Born solvation models and temperature control schemes. The improvements in both the force field and solvent model allowed successful simulations of the folding process to the native state as demonstrated by the 0.80 angstrom C-alpha root mean square deviation (RMSD) of the best folded structure. The most populated conformation was the native folded structure with a high population. This was a significant improvement over the 2.8 angstrom C-alpha RMSD of the best nativelike structures from previous ab initio folding studies on BdpA. To the best of our knowledge, our results demonstrate, for the first time, that ab initio simulations can reach the native state of BdpA. Consistent with experimental observations, including Phi-value analyses, formation of helix II/III hairpin was a crucial step that provides a template upon which helix I could form and the folding process could complete. Early formation of helix III was observed which is consistent with the experimental results of higher residual helical content of isolated helix III among the three helices. The calculated temperature-dependent profile and the melting temperature were in close agreement with the experimental results. The simulations further revealed that phenylalanine 31 may play critical to achieve the correct packing of the three helices which is consistent with the experimental observation. In addition to the mechanistic studies, an ab initio structure prediction was also conducted based on both the physical energy and a statistical potential. Based on the lowest physical energy, the predicted structure was 2.0 angstrom C-alpha RMSD away from the experimentally determined structure. (C) 2008 American Institute of Physics.