Statistical mechanics of protein allostery: Roles of backbone and side-chain structural fluctuations

• Published in: The Journal of chemical physics 2011-03, Vol.134 (12), p.125102-125102-19
• Main Authors: Itoh, Kazuhito, Sasai, Masaki
• Format: Article
• Language: English
• Subjects: Allosteric Regulation; Animals; Calcium - metabolism; Calmodulin - chemistry; Calmodulin - metabolism; Entropy; Guanosine Diphosphate - metabolism; Guanosine Triphosphate - metabolism; Humans; Methyltransferases - chemistry; Methyltransferases - metabolism; Models, Biological; Models, Molecular; Models, Statistical; Protein Binding; Protein Conformation; Proteins - chemistry; Proteins - metabolism; ras Proteins - chemistry; ras Proteins - metabolism
• ISSN: 0021-9606; 1089-7690
• DOI: 10.1063/1.3565025

A statistical mechanical model of allosteric transition of proteins is developed by extending the structure-based model of protein folding to cases that a protein has two different native conformations. Partition function is calculated exactly within the model and free-energy surfaces associated with allostery are derived. In this paper, the model of allosteric transition proposed in a previous paper [ Proc. Natl. Acad. Sci. U.S.A 134 , 7775 ( 2010 ) ] is reformulated to describe both fluctuation in side-chain configurations and that in backbone structures in a balanced way. The model is applied to example proteins, Ras, calmodulin, and CheY: Ras undergoes the allosteric transition between guanosine diphosphate (GDP)-bound and guanosine triphosphate (GTP)-bound forms, and the model results show that the GDP-bound form is stabilized enough to prevent unnecessary signal transmission, but the conformation in the GTP-bound state bears large fluctuation in side-chain configurations, which may help to bind multiple target proteins for multiple pathways of signaling. The calculated results of calmodulin show the scenario of sequential ordering in Ca 2 + binding and the associated allosteric conformational change, which are realized though the sequential appearing of pre-existing structural fluctuations, i.e., fluctuations to show structures suitable to bind Ca 2 + before its binding. Here, the pre-existing fluctuations to accept the second and third Ca 2 + ions are dominated by the side-chain fluctuation. In CheY, the calculated side-chain fluctuation of Tyr106 is coordinated with the backbone structural change in the β4-α4 loop, which explains the pre-existing Y-T coupling process in this protein. Ability of the model to explain allosteric transitions of example proteins supports the view that the large entropic effects lower the free-energy barrier of allosteric transition.