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Biomolecules 2014, 4(1), 291-314; doi:10.3390/biom4010291
Review

Detecting Selection on Protein Stability through Statistical Mechanical Models of Folding and Evolution

Received: 25 December 2013; in revised form: 13 February 2014 / Accepted: 14 February 2014 / Published: 7 March 2014
(This article belongs to the Special Issue Protein Folding and Misfolding)
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Abstract: The properties of biomolecules depend both on physics and on the evolutionary process that formed them. These two points of view produce a powerful synergism. Physics sets the stage and the constraints that molecular evolution has to obey, and evolutionary theory helps in rationalizing the physical properties of biomolecules, including protein folding thermodynamics. To complete the parallelism, protein thermodynamics is founded on the statistical mechanics in the space of protein structures, and molecular evolution can be viewed as statistical mechanics in the space of protein sequences. In this review, we will integrate both points of view, applying them to detecting selection on the stability of the folded state of proteins. We will start discussing positive design, which strengthens the stability of the folded against the unfolded state of proteins. Positive design justifies why statistical potentials for protein folding can be obtained from the frequencies of structural motifs. Stability against unfolding is easier to achieve for longer proteins. On the contrary, negative design, which consists in destabilizing frequently formed misfolded conformations, is more difficult to achieve for longer proteins. The folding rate can be enhanced by strengthening short-range native interactions, but this requirement contrasts with negative design, and evolution has to trade-off between them. Finally, selection can accelerate functional movements by favoring low frequency normal modes of the dynamics of the native state that strongly correlate with the functional conformation change.
Keywords: protein folding; misfolding; negative design; protein evolution; natural selection protein folding; misfolding; negative design; protein evolution; natural selection
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Bastolla, U. Detecting Selection on Protein Stability through Statistical Mechanical Models of Folding and Evolution. Biomolecules 2014, 4, 291-314.

AMA Style

Bastolla U. Detecting Selection on Protein Stability through Statistical Mechanical Models of Folding and Evolution. Biomolecules. 2014; 4(1):291-314.

Chicago/Turabian Style

Bastolla, Ugo. 2014. "Detecting Selection on Protein Stability through Statistical Mechanical Models of Folding and Evolution." Biomolecules 4, no. 1: 291-314.


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