title: Statistical mechanics of protein allostery: roles of backbone and side-chain structural fluctuations.
abstract: 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.
authors: Department of Applied Physics, Nagoya University, Nagoya 464-8603, Japan. kazuhito@tbp.cse.nagoya-u.ac.jp
authors: Kazuhito
authors: K
authors: Itoh
authors: Masaki
authors: M
authors: Sasai
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000737:chemistry / Q000378:metabolism; D019277:Entropy; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D008780:Methyltransferases / Q000737:chemistry / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D015233:Models, Statistical; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D018631:ras Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D002147:Calmodulin; D011506:Proteins; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D008780:Methyltransferases; D018631:ras Proteins; D002118:Calcium