Document Detail


De novo prediction of protein folding pathways and structure using the principle of sequential stabilization.
MedLine Citation:
PMID:  23045636     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Motivated by the relationship between the folding mechanism and the native structure, we develop a unified approach for predicting folding pathways and tertiary structure using only the primary sequence as input. Simulations begin from a realistic unfolded state devoid of secondary structure and use a chain representation lacking explicit side chains, rendering the simulations many orders of magnitude faster than molecular dynamics simulations. The multiple round nature of the algorithm mimics the authentic folding process and tests the effectiveness of sequential stabilization (SS) as a search strategy wherein 2° structural elements add onto existing structures in a process of progressive learning and stabilization of structure found in prior rounds of folding. Because no a priori knowledge is used, we can identify kinetically significant non-native interactions and intermediates, sometimes generated by only two mutations, while the evolution of contact matrices is often consistent with experiments. Moreover, structure prediction improves substantially by incorporating information from prior rounds. The success of our simple, homology-free approach affirms the validity of our description of the primary determinants of folding pathways and structure, and the effectiveness of SS as a search strategy.
Authors:
Aashish N Adhikari; Karl F Freed; Tobin R Sosnick
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, P.H.S.     Date:  2012-10-08
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  109     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-24     Completed Date:  2013-01-07     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  17442-7     Citation Subset:  IM    
Affiliation:
Department of Chemistry, University of Chicago, Chicago, IL 60637, USA.
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MeSH Terms
Descriptor/Qualifier:
Algorithms
Kinetics
Molecular Dynamics Simulation
Monte Carlo Method
Protein Folding*
Protein Structure, Secondary*
Grant Support
ID/Acronym/Agency:
GM55694/GM/NIGMS NIH HHS; S10 RR029030-01/RR/NCRR NIH HHS
Comments/Corrections

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