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Simulation of coupled folding and binding of an intrinsically disordered protein in explicit solvent with metadynamics
Han, Mengzhi1,2; Xu, Ji1; Ren, Ying1; Li, Jinghai1
2016-07-01
Source PublicationJOURNAL OF MOLECULAR GRAPHICS & MODELLING
ISSN1093-3263
Volume68Issue:JULYPages:114-127
Abstract

The C-terminal domain of measles virus nucleoprotein is an intrinsically disordered protein that could bind to the X domain (XD) of phosphoprotein P to exert its physiological function. Experiments reveal that the minimal binding unit is a 21-residue alpha-helical molecular recognition element (alpha-MORE-MeV), which adopts a fully helical conformation upon binding to XD. Due to currently limited computing power, direct simulation of this coupled folding and binding process with atomic force field in explicit solvent cannot be achieved. In this work, two advanced sampling methods, metadynamics and parallel tempering, are combined to characterize the free energy surface of this process and investigate the underlying mechanism. Starting from an unbound and partially folded state of alpha-MoRE-MeV, multiple folding and binding events are observed during the simulation and the energy landscape was well estimated. The results demonstrate that the isolated alpha-MORE-MeV resembles a molten globule and rapidly interconverts between random coil and multiple partially helical states in solution. The coupled folding and binding process occurs through the induced fit mechanism, with the residual helical conformations providing the initial binding sites. Upon binding, alpha-MORE-MeV can easily fold into helical conformation without obvious energy barriers. Two mechanisms, namely, the system tending to adopt the structure in which the free energy of isolated alpha-MORE-MeV is the minimum, and the binding energy of alpha-MoRE-MeV to its partner protein XD tending to the minimum, jointly dominate the coupled folding and binding process. With the advanced sampling approach, more IDP systems could be simulated and common mechanisms concerning the coupled folding and binding process could be investigated in the future. (C) 2016 Published by Elsevier Inc.

KeywordMeasles Virus Nucleoprotein Intrinsically Disordered Protein Coupled Folding And Binding Molecular Dynamics Metadynamics Free Energy Surface
SubtypeArticle
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine ; Technology ; Physical Sciences
DOI10.1016/j.jmgm.2016.06.015
Indexed BySCI
Language英语
WOS KeywordC-TERMINAL DOMAIN ; MEASLES-VIRUS NUCLEOPROTEIN ; MOLECULAR-DYNAMICS SIMULATION ; FREE-ENERGY LANDSCAPE ; LINEAR CONSTRAINT SOLVER ; PARTICLE MESH EWALD ; UNSTRUCTURED PROTEINS ; EPR SPECTROSCOPY ; HUMAN-DISEASES ; PHOSPHOPROTEIN
WOS Research AreaBiochemistry & Molecular Biology ; Computer Science ; Crystallography ; Mathematical & Computational Biology
WOS SubjectBiochemical Research Methods ; Biochemistry & Molecular Biology ; Computer Science, Interdisciplinary Applications ; Crystallography ; Mathematical & Computational Biology
Funding OrganizationNational Natural Science Foundation of China(21103195 ; Ministry of Science and Technology of China(COM2015A003) ; 91434104)
WOS IDWOS:000382351400013
Citation statistics
Cited Times:5[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.ipe.ac.cn/handle/122111/21447
Collection多相复杂系统国家重点实验室
Affiliation1.Chinese Acad Sci, IPE, State Key Lab Multiphase Complex Syst, Beijing 100190, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
Recommended Citation
GB/T 7714
Han, Mengzhi,Xu, Ji,Ren, Ying,et al. Simulation of coupled folding and binding of an intrinsically disordered protein in explicit solvent with metadynamics[J]. JOURNAL OF MOLECULAR GRAPHICS & MODELLING,2016,68(JULY):114-127.
APA Han, Mengzhi,Xu, Ji,Ren, Ying,&Li, Jinghai.(2016).Simulation of coupled folding and binding of an intrinsically disordered protein in explicit solvent with metadynamics.JOURNAL OF MOLECULAR GRAPHICS & MODELLING,68(JULY),114-127.
MLA Han, Mengzhi,et al."Simulation of coupled folding and binding of an intrinsically disordered protein in explicit solvent with metadynamics".JOURNAL OF MOLECULAR GRAPHICS & MODELLING 68.JULY(2016):114-127.
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