Document Detail


Kinetics and reaction coordinates of the reassembly of protein fragments via forward flux sampling.
MedLine Citation:
PMID:  20441755     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We studied the mechanism of the reassembly and folding process of two fragments of a split lattice protein by using forward flux sampling (FFS). Our results confirmed previous thermodynamics and kinetics analyses that suggested that the disruption of the critical core (of an unsplit protein that folds by a nucleation mechanism) plays a key role in the reassembly mechanism of the split system. For several split systems derived from a parent 48-mer model, we estimated the reaction coordinates in terms of collective variables by using the FFS least-square estimation method and found that the reassembly transition is best described by a combination of the total number of native contacts, the number of interchain native contacts, and the total conformational energy of the split system. We also analyzed the transition path ensemble obtained from FFS simulations using the estimated reaction coordinates as order parameters to identify the microscopic features that differentiate the reassembly of the different split systems studied. We found that in the fastest folding split system, a balanced distribution of the original-core amino acids (of the unsplit system) between protein fragments propitiates interchain interactions at early stages of the folding process. Only this system exhibits a different reassembly mechanism from that of the unsplit protein, involving the formation of a different folding nucleus. In the slowest folding system, the concentration of the folding nucleus in one fragment causes its early prefolding, whereas the second fragment tends to remain as a detached random coil. We also show that the reassembly rate can be either increased or decreased by tuning interchain cooperativeness via the introduction of a single point mutation that either strengthens or weakens one of the native interchain contacts (prevalent in the transition state ensemble).
Authors:
Ernesto E Borrero; Lydia M Contreras Martínez; Matthew P DeLisa; Fernando A Escobedo
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Biophysical journal     Volume:  98     ISSN:  1542-0086     ISO Abbreviation:  Biophys. J.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-05-05     Completed Date:  2010-07-29     Revised Date:  2011-07-28    
Medline Journal Info:
Nlm Unique ID:  0370626     Medline TA:  Biophys J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1911-20     Citation Subset:  IM    
Copyright Information:
Copyright (c) 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.
Affiliation:
School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, USA.
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MeSH Terms
Descriptor/Qualifier:
Kinetics
Models, Molecular
Peptide Fragments / chemistry,  metabolism*
Probability
Protein Binding
Protein Conformation
Protein Denaturation
Protein Folding*
Thermodynamics
Chemical
Reg. No./Substance:
0/Peptide Fragments
Comments/Corrections

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