title: Comparing allosteric transitions in the domains of calmodulin through coarse-grained simulations.
abstract: Calmodulin (CaM) is a ubiquitous Ca(2+)-binding protein consisting of two structurally similar domains with distinct stabilities, binding affinities, and flexibilities. We present coarse grained simulations that suggest that the mechanism for the domain's allosteric transitions between the open and closed conformations depends on subtle differences in the folded state topology of the two domains. Throughout a wide temperature range, the simulated transition mechanism of the N-terminal domain (nCaM) follows a two-state transition mechanism while domain opening in the C-terminal domain (cCaM) involves unfolding and refolding of the tertiary structure. The appearance of the unfolded intermediate occurs at a higher temperature in nCaM than it does in cCaM consistent with nCaM's higher thermal stability. Under approximate physiological conditions, the simulated unfolded state population of cCaM accounts for 10% of the population with nearly all of the sampled transitions (approximately 95%) unfolding and refolding during the conformational change. Transient unfolding significantly slows the domain opening and closing rates of cCaM, which can potentially influence its Ca(2+)-binding mechanism.
authors.affiliation: Department of Physics, Kent State University, Kent, Ohio 44242, USA.
authors.forename: Prithviraj
authors.initials: P
authors.lastname: Nandigrami
authors.affiliation: Department of Physics, Kent State University, Kent, Ohio 44242, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Portman
mesh_terms: D000494:Allosteric Regulation; D002118:Calcium / Q000737:chemistry; D002147:Calmodulin / Q000737:chemistry*; D003198:Computer Simulation; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D000072417:Protein Domains; D058849:Protein Refolding; D058767:Protein Unfolding
chemical_list: D002147:Calmodulin; D002118:Calcium