title: Response of small-scale, methyl rotors to protein-ligand association: a simulation analysis of calmodulin-peptide binding.
abstract: Changes in the free energy barrier (DeltaE), entropy, and motional parameters associated with the rotation of methyl groups in a protein (calmodulin (CaM)) on binding a ligand (the calmodulin-binding domain of smooth-muscle myosin (smMLCKp)) are investigated using molecular dynamics simulation. In both the bound and uncomplexed forms of CaM, the methyl rotational free energy barriers follow skewed-Gaussian distributions that are not altered significantly upon ligand binding. However, site-specific perturbations are found. Around 11% of the methyl groups in CaM exhibit changes in DeltaE greater than 0.7 kcal/mol on binding. The rotational entropies of the methyl groups exhibit a nonlinear dependence on DeltaE. The relations are examined between motional parameters (the methyl rotational NMR order parameter and the relaxation time) and DeltaE. Low-barrier methyl group rotational order parameters deviate from ideal tetrahedrality by up to approximately 20%. There is a correlation between rotational barrier changes and proximity to the protein-peptide binding interface. Methyl groups that exhibit large changes in DeltaE are found to report on elements in the protein undergoing structural change on binding.
authors.affiliation: UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, USA. krishnanm@ornl.gov
authors.forename: Marimuthu
authors.initials: M
authors.lastname: Krishnan
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Smith
mesh_terms: D002147:Calmodulin / Q000737:chemistry* / Q000378:metabolism; D003198:Computer Simulation; D008024:Ligands; D008745:Methylation; D008956:Models, Chemical; D008958:Models, Molecular; D009218:Myosins / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D015203:Reproducibility of Results; D013816:Thermodynamics
chemical_list: D002147:Calmodulin; D008024:Ligands; D009218:Myosins