title: High-Dimensional Mutant and Modular Thermodynamic Cycles, Molecular Switching, and Free Energy Transduction.
abstract: Understanding how distinct parts of proteins produce coordinated behavior has driven and continues to drive advances in protein science and enzymology. However, despite consensus about the conceptual basis for allostery, the idiosyncratic nature of allosteric mechanisms resists general approaches. Computational methods can identify conformational transition states from structural changes, revealing common switching mechanisms that impose multistate behavior. Thermodynamic cycles use factorial perturbations to measure coupling energies between side chains in molecular switches that mediate shear during domain motion. Such cycles have now been complemented by modular cycles that measure energetic coupling between separable domains. For one model system, energetic coupling between domains has been shown to be quantitatively equivalent to that between dynamic side chains. Linkages between domain motion, switching residues, and catalysis make nucleoside triphosphate hydrolysis conditional on domain movement, confirming an essential yet neglected aspect of free energy transduction and suggesting the potential generality of these studies.
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514; email: carter@med.unc.edu.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Carter
mesh_terms: D000494:Allosteric Regulation; D055162:Biocatalysis; D006868:Hydrolysis; D015640:Ion Channel Gating; D008954:Models, Biological; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D009711:Nucleotides / Q000737:chemistry* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated / Q000737:chemistry / Q000235:genetics; D000072417:Protein Domains; D013816:Thermodynamics; D014369:Tryptophan-tRNA Ligase / Q000737:chemistry / Q000235:genetics
chemical_list: D009711:Nucleotides; D024642:Potassium Channels, Voltage-Gated; D014369:Tryptophan-tRNA Ligase
keywords: catalysis; domain motion; tryptophanyl-tRNA synthetase; voltage-gated K+ channel