Exploring Transition Pathway and Free-Energy Profile of Large-Scale Protein Conformational Change by Combining Normal Mode Analysis and Umbrella Sampling Molecular Dynamics
文献类型：期刊论文
| 作者 | Wang, Jinan1; Shao, Qiang1 ; Xu, Zhijian1; Liu, Yingtao1; Yang, Zhuo1; Cossins, Benjamin P.2; Jiang, Hualiang1; Chen, Kaixian1; Shi, Jiye2; Zhu, Weiliang1
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| 刊名 | JOURNAL OF PHYSICAL CHEMISTRY B
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| 出版日期 | 2014-01-09 |
| 卷号 | 118期号:1页码:134-143 |
| ISSN号 | 1520-6106 |
| DOI | 10.1021/jp4105129 |
| 文献子类 | Article |
| 英文摘要 | Large-scale conformational changes of proteins are usually associated with the binding of ligands. Because the conformational changes are often related to the biological functions of proteins, understanding the molecular mechanisms of these motions and the effects of ligand binding becomes very necessary. In the present study, we use the combination of normal-mode analysis and umbrella sampling molecular dynamics simulation to delineate the atomically detailed conformational transition pathways and the associated free-energy landscapes for three well-known protein systems, viz., adenylate kinase (AdK), calmodulin (CaM), and p38 alpha kinase in the absence and presence of respective ligands. For each protein under study, the transient conformations along the conformational transition pathway and thermodynamic observables are in agreement with experimentally and computationally determined ones. The calculated free-energy profiles reveal that AdK and CaM are intrinsically flexible in structures without obvious energy barrier, and their ligand binding shifts the equilibrium from the ligand-free to ligand-bound conformation (population shift mechanism). In contrast, the ligand binding to p38 alpha leads to a large change in free-energy barrier (Delta Delta G approximate to 7 kcal/mol), promoting the transition from DFG-in to DFG-out conformation (induced fit mechanism). Moreover, the effect of the protonation of D168 on the conformational change of p38 alpha is also studied, which reduces the free-energy difference between the two functional states of p38 alpha and thus further facilitates the conformational interconversion. Therefore, the present study suggests that the detailed mechanism of ligand binding and the associated conformational transition is not uniform for all kinds of proteins but correlated to their respective biological functions. |
| WOS关键词 | PRINCIPAL COMPONENT ANALYSIS ; COMPUTER-SIMULATION ANALYSIS ; HISTOGRAM ANALYSIS METHOD ; P38 MAP KINASE ; ADENYLATE KINASE ; LIGAND-BINDING ; SHIFT MECHANISM ; CALCIUM SENSOR ; FORCE-FIELD ; CALMODULIN |
| 资助项目 | National 863 Program[2012AA01A305] ; National Natural Science Foundation of China (NNSFC)[21373258] ; National Natural Science Foundation of China (NNSFC)[21021063] ; National Natural Science Foundation of China (NNSFC)[81273435] ; National Basic Research Program of China (973)[2012CB910403] |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000329678000014 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277233]  |
| 专题 | 药物发现与设计中心 |
| 通讯作者 | Shao, Qiang |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China; 2.UCB Pharma, Slough SL1 3WE, Berks, England |
| 推荐引用方式 GB/T 7714 | Wang, Jinan,Shao, Qiang,Xu, Zhijian,et al. Exploring Transition Pathway and Free-Energy Profile of Large-Scale Protein Conformational Change by Combining Normal Mode Analysis and Umbrella Sampling Molecular Dynamics[J]. JOURNAL OF PHYSICAL CHEMISTRY B,2014,118(1):134-143. |
| APA | Wang, Jinan.,Shao, Qiang.,Xu, Zhijian.,Liu, Yingtao.,Yang, Zhuo.,...&Zhu, Weiliang.(2014).Exploring Transition Pathway and Free-Energy Profile of Large-Scale Protein Conformational Change by Combining Normal Mode Analysis and Umbrella Sampling Molecular Dynamics.JOURNAL OF PHYSICAL CHEMISTRY B,118(1),134-143. |
| MLA | Wang, Jinan,et al."Exploring Transition Pathway and Free-Energy Profile of Large-Scale Protein Conformational Change by Combining Normal Mode Analysis and Umbrella Sampling Molecular Dynamics".JOURNAL OF PHYSICAL CHEMISTRY B 118.1(2014):134-143. |
入库方式： OAI收割
来源：上海药物研究所
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