Kinetics, thermodynamics and evolution of non-native interactions in a protein folding nucleus.

L Li, L A Mirny, E I Shakhnovich

Journal: Nature structural biology 2000;7(4):336-42

PMID: 10742180

Abstract

A lattice model with side chains was used to investigate protein folding with computer simulations. In this model, we rigorously demonstrate the existence of a specific folding nucleus. This nucleus contains specific interactions not present in the native state that, when weakened, slow folding but do not change protein stability. Such a decoupling of folding kinetics from thermodynamics has been observed experimentally for real proteins. From our results, we conclude that specific non-native interactions in the transition state would give rise to straight phi-values that are negative or larger than unity. Furthermore, we demonstrate that residue Ile 34 in src SH3, which has been shown to be kinetically, but not thermodynamically, important, is universally conserved in proteins with the SH3 fold. This is a clear example of evolution optimizing the folding rate of a protein independent of its stability and function.

Address: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.

DOI: 10.1038/74111

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MeSH Terms: Amino Acid Sequence, Amino Acid Substitution, Binding Sites, Computer Simulation, Conserved Sequence, Enzyme Stability, Evolution, Molecular, Kinetics, Models, Chemical, Models, Molecular, Molecular Sequence Data, Monte Carlo Method, Mutation, Protein Folding, Proteins, Proto-Oncogene Proteins pp60(c-src), Sequence Alignment, Thermodynamics, src Homology Domains