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Time‐resolved backbone desolvation and mutational hot spots in folding proteins
Author(s) -
Fernández Ariel
Publication year - 2002
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.10109
Subject(s) - hydrogen bond , chemistry , folding (dsp implementation) , protein folding , nucleation , contact order , crystallography , chemical physics , phi value analysis , intramolecular force , native state , molecule , stereochemistry , biochemistry , organic chemistry , electrical engineering , engineering
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 Φ‐value analysis on chymotrypsin inhibitor 2, a protein for which extensive mutational data exists. Proteins 2002;47:447–457. © 2002 Wiley‐Liss, Inc.