Molecular Dynamics Simulations and Steered Molecular Dynamics Simulations of Glabridin Bound to Wild Type and V30A Mutant Transthyretin： Ligand-linked Perturbation of Tertiary Conformation  

作　　者：YU Zhengfei HAN Jiarui LIU Ye ZHU Jingxuan TIAN Xiaopian HAN Weiwei 

机构地区：[1]Key Laboratory for Molecular Enzymology and Engineering, Ministry of Education, School of Life Sciences Jilin University, Changchun 130012, P. R. China

出　　处：《Chemical Research in Chinese Universities》2018年第6期995-1003,共9页高等学校化学研究（英文版）

基　　金：Supported by the Major Scientific Research Projects of Jilin Province, China（No.20140203025NY） and the Natural Science Foundation of Jilin Province, China（No. 3B812C201465）.

摘　　要：Transthyretin（TTR）, as a tetrameric protein, functions as a neuroprotector. The native TTR homotetramer dissociates into dimers and monomers. Dimers and monomers self-assemble into amyloid fibrils, and this process can lead to some diseases. Native TTR homotetramer is a widely accepted model for TTR amyloid formation. In this study, simulations using molecular dynamics（MD） and steered MD（SMD） were performed to explore the mechanisms for glabridin（Glab）, a specific inhibitor for TTR binding, for V30A mutant and wild-type（WT） TTR. MD simulation results indicate that, compared with Glab binding to WT and V30A mutant, the WT TTR could lead to the collapse of β-strands from Ser52 to His56 at chain A. This phenomenon facilitated the easy dissociation of chains A and C. Calculations of the binding free energy between the two chains showed that the V30A-Glab TTR complex displayed a lower binding energy than other systems（WT TTR and WT-Glab TTR）. Then, SMD simulation was performed to ex- plore the unbinding pathway for Glab through the WT and V30A mutant TTR. The results show that Lysl 5（chain A） produced a hydrogen bond with Glab at the force peak via the WT TTR tunnel. Meanwhile, in the V30A TTR mutant, the hydrogen bond between Lysl 5（chain A） and Glab was broken at the force peak. This condition was beneficial for Glab to be taken off from the protein. Our theoretical results will be useful in designing a new specific inhibitor of TTR protein to control the TTR homotetramer dissociation.Transthyretin（TTR）, as a tetrameric protein, functions as a neuroprotector. The native TTR homotetramer dissociates into dimers and monomers. Dimers and monomers self-assemble into amyloid fibrils, and this process can lead to some diseases. Native TTR homotetramer is a widely accepted model for TTR amyloid formation. In this study, simulations using molecular dynamics（MD） and steered MD（SMD） were performed to explore the mechanisms for glabridin（Glab）, a specific inhibitor for TTR binding, for V30A mutant and wild-type（WT） TTR. MD simulation results indicate that, compared with Glab binding to WT and V30A mutant, the WT TTR could lead to the collapse of β-strands from Ser52 to His56 at chain A. This phenomenon facilitated the easy dissociation of chains A and C. Calculations of the binding free energy between the two chains showed that the V30A-Glab TTR complex displayed a lower binding energy than other systems（WT TTR and WT-Glab TTR）. Then, SMD simulation was performed to ex- plore the unbinding pathway for Glab through the WT and V30A mutant TTR. The results show that Lysl 5（chain A） produced a hydrogen bond with Glab at the force peak via the WT TTR tunnel. Meanwhile, in the V30A TTR mutant, the hydrogen bond between Lysl 5（chain A） and Glab was broken at the force peak. This condition was beneficial for Glab to be taken off from the protein. Our theoretical results will be useful in designing a new specific inhibitor of TTR protein to control the TTR homotetramer dissociation.

关 键 词：TRANSTHYRETIN GLABRIDIN Conformational change Molecular mechanics-poisson Boltzmann surface area（MM-PBSA） 

分 类 号：O561.3[理学—原子与分子物理] TQ028.32[理学—物理]