M<sup>pro</sup>-C蛋白三维结构域交换的机理: 来自分子模拟的线索

引用本文: 黄永棋, 康雪, 夏斌, 刘志荣. M^pro-C蛋白三维结构域交换的机理: 来自分子模拟的线索[J]. 物理化学学报, 2012, 28(10): 2411-2417. doi: 10.3866/PKU.WHXB201209072 shu

Citation: HUANG Yong-Qi, KANG Xue, XIA Bing, LIU Zhi-Rong. Mechanism of 3D Domain Swapping for M^pro-C: Clues from Molecular Simulations[J]. Acta Physico-Chimica Sinica, 2012, 28(10): 2411-2417. doi: 10.3866/PKU.WHXB201209072 shu

M^pro-C蛋白三维结构域交换的机理: 来自分子模拟的线索

基金项目:
国家重点基础研究发展计划项目(973) (2009CB918500, 2003CB514104) (973) (2009CB918500, 2003CB514104)

国家自然科学基金(20973016, 10721403, 31170682)资助 (20973016, 10721403, 31170682)

摘要:

SARS冠状病毒主蛋白酶(M^pro)在病毒的蛋白酶切过程中发挥着重要作用. M^pro的晶体结构显示它存在两种形式的二聚体: 一种是发生三维结构域交换的形式, 另一种是非交换的形式. M^pro的C端结构域(M^pro-C)单独表达时也能形成与全长M^pro类似的三维结构域交换二聚体. 三维结构域交换通常发生在蛋白质的表面, 但M^pro-C 的结构域交换却发生在疏水核心. 在本文中, 我们利用分子动力学模拟及三维结构域交换预测算法研究了M^pro-C 中被高度埋藏的核心螺旋片段发生交换的机理. 我们发现基于结构与基于序列的已有算法都不能正确预言出M^pro-C和M^pro中发生结构域交换的铰链区位置. 分子模拟结果表明M^pro-C中的交换片段在天然态下埋藏得很好, 但在变性单体中则会被释放并暴露在外面. 因此, 在完全或部分解折叠状态下交换片段的打开有助于促进单体间的相互作用及结构域交换二聚体的形成.

关键词:

English

Mechanism of 3D Domain Swapping for M^pro-C: Clues from Molecular Simulations

1.
1 College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, P. R. China;
2 State Key Laboratory for Structural Chemistry of Unstable and Stable Species and Beijing National Laboratory for Molecular Sciences (BNLMS), Peking University, Beijing 100871, P. R. China;
3 Center for Quantitative Biology, Peking University, Beijing 100871, P. R. China;
4 Beijing Nuclear Magnetic Resonance Center, Peking University, Beijing 100871, P. R. China;
5 School of Life Sciences, Peking University, Beijing 100871, P. R. China
Received Date: 13 August 2012
Available Online: 26 September 2012
Fund Project:
国家重点基础研究发展计划项目(973) (2009CB918500, 2003CB514104)

国家自然科学基金(20973016, 10721403, 31170682)资助

Abstract:

SARS coronavirus main protease (M^pro) is a key enzyme involved in the extensive proteolytic processing of the virus? polyproteins. The crystal structure of M^pro reveals that the enzyme exists in two different homo-dimeric forms: a three-dimensional (3D) domain-swapped form; and a non-3D domain-swapped form. The isolated C-terminal domain (M^pro-C) also forms a 3D domain-swapped structure similar to the full-length protein. Unlike conventional 3D domain-swapped structures, in which the swapped regions are located on the surface, M^pro-C swaps a helix at the core of a folded domain. In this work, we used molecular dynamics simulations and 3D domain-swapping predictions to investigate how a highly buried core helix in the helix bundle structure of M^pro-C can be swapped. We found that both structure- and sequence-based methods failed to predict the location of the hinge loop in M^pro-C and M^pro. Extensive molecular dynamics simulations were performed to investigate the structural properties of the unfolded monomer and the 3D domain-swapped dimer of M^pro-C. We found that, although the swapped region was buried in the native state, it was exposed in the unfolded monomer. Our results suggest that the opening of the swapped region in the fully or partially unfolded state may promote interactions between monomers and the formation of domain-swapped dimers.

Key words:

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1.
沈阳化工大学材料科学与工程学院沈阳 110142

M^pro-C蛋白三维结构域交换的机理: 来自分子模拟的线索

English

Mechanism of 3D Domain Swapping for M^pro-C: Clues from Molecular Simulations

CCS Chemistry：嵌段共聚物自组装成 “三明治”二维有机材料，实现纳米级压力传感功能

CCS Chemistry：颜徐州、鲍哲南：你的皮肤可能是一片SPMs

CCS Chemistry：工作高效不疲劳，只须让催化剂动起来

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通讯作者: 陈斌, bchen63@163.com

中国化学会秘书处

Mpro-C蛋白三维结构域交换的机理: 来自分子模拟的线索

English

Mechanism of 3D Domain Swapping for Mpro-C: Clues from Molecular Simulations

CCS Chemistry：嵌段共聚物自组装成 “三明治”二维有机材料，实现纳米级压力传感功能

CCS Chemistry：颜徐州、鲍哲南： 你的皮肤可能是一片SPMs

CCS Chemistry：工作高效不疲劳，只须让催化剂动起来

CCS Chemistry：静电组装导向聚合- 聚电解质纳米凝胶量化制备新策略

CCS Chemistry：金黄色葡萄球菌醛基脱氢酶是如何识别特异性底物的？

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通讯作者: 陈斌, bchen63@163.com

中国化学会秘书处

M^pro-C蛋白三维结构域交换的机理: 来自分子模拟的线索

Mechanism of 3D Domain Swapping for M^pro-C: Clues from Molecular Simulations

CCS Chemistry：颜徐州、鲍哲南：你的皮肤可能是一片SPMs