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1: Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10382-7. Epub 2002 Jul 29.
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Roles of mutation and recombination in the evolution of protein thermodynamics.

Xia Y, Levitt M.

Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. yuxia@csb.stanford.edu

We present a comprehensive study of the evolutionary origin of the thermodynamic behavior of proteins. With the use of a simplified model, we exhaustively enumerate the space of all sequences and the space of all structures, simulate the evolutionary relationship between sequences and structures, and characterize the steady-state sequence distribution for all structures in terms of several thermodynamic variables. We assess the effects of two major forces of evolution: mutation and recombination. Three simplifications are made. First, a two-dimensional lattice model is used to represent protein sequences and structures. Second, proteins undergo neutral evolution so that the fitness landscape has a flat allowed region inside of which all sequences are equally fit. Third, we ignore otherwise important factors such as finite population size and evolutionary time. Two scenarios emerge from our study. The first occurs when evolution is dominated by mutation events. Even though the prototype sequence that is most mutationally robust is preferred by evolution, the preference is not strong enough to offset the huge size of sequence space. Most native sequences are located near the boundary of the fitness region and are marginally compatible with the native structure. The second scenario occurs when evolution is dominated by recombination events. Now evolutionary preference for prototype sequence is strong enough to overcome the size of sequence space so that most native sequences are located near the center of sequence-structure compatibility. We conclude that the relative frequency of mutation and recombination events is a major determinant of how optimal protein sequences are for their structures.

Publication Types:
PMID: 12149452 [PubMed - indexed for MEDLINE]

PMCID: PMC124923