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  Time-resolved backbone desolvation and mutational hot spots in folding proteins

Fernandez, A. (2002). Time-resolved backbone desolvation and mutational hot spots in folding proteins. Proteins-Structure Function and Genetics, 47(4), 447-457.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-6F0C-0 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-6F0D-E
Genre: Journal Article
Alternative Title : Proteins

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 Creators:
Fernandez, A.1, Author              
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1External Organizations, ou_persistent22              

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Free keywords: ab initio simulations; chymotrypsin inhibitor 2; mammalian ubiquitin
 Abstract: A method is presented to identify hot mutational spots and predict the extent of surface burial at the transition state relative to the native fold in two-state folding proteins. The method is based on ab initio simulations of folding histories in which transitions between coarsely defined conformations and pairwise interactions are dependent on the solvent environments created by the chain. The highly conserved mammalian ubiquitin is adopted as a study case to make predictions. The evolution in time of the chain topology suggests a nucleation process with a critical point signaled by a sudden quenching of structural fluctuations. The occurrence of this nucleus is shown to be concurrent with a sudden escalation in the number of three-body correlations whereby hydrophobic units approach residue pairs engaged in amide-carbonyl hydrogen bonding. These correlations determine a pattern designed to structure the surrounding solvent, protecting intramolecular hydrogen bonds from water attack. Such correlations are shown to be required to stabilize the nucleus, with kinetic consequences for the folding process. Those nuclear residues that adopt the dual role of protecting and being protected while engaged in hydrogen bonds are predicted to be the hottest mutational spots. Some such residues are shown not to retain the same protecting role in the native fold. This kinetic treatment of folding nucleation is independently validated vis-a-vis a Phi- value analysis on chymotrypsin inhibitor 2, a protein for which extensive mutational data exists.

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Language(s): eng - English
 Dates: 2002-06-01
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: eDoc: 28926
ISI: 000175911400002
 Degree: -

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Title: Proteins-Structure Function and Genetics
  Alternative Title : Proteins
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: -
Pages: - Volume / Issue: 47 (4) Sequence Number: - Start / End Page: 447 - 457 Identifier: ISSN: 0887-3585