title: Statistical allosteric coupling to the active site indole ring flip equilibria in the FK506-binding domain.
abstract: In solution, the Trp 59 indole ring at the base of the active site cleft in the FKBP domain protein FKBP12 is rotated by ~90° at a population level of 20%, relative to its canonical crystallographic orientation. NMR measurements on the homologous FK1 domains of human FKBP51 and FKBP52 indicate no observable indole ring flip conformation, while the V101I variant of FKBP12 decreases the population having a perpendicular indole orientation by 10-fold. A set of three parallel 400 ns CHARMM27 molecular simulations for both wild type FKBP12 and the V101I variant examined how this ring flip might be energetically coupled to a transition of the Glu 60 sidechain which interacts with the backbone of the 50's loop located ~12 Å from the indole nitrogen. Analysis of the transition matrix for the local dynamics of the Glu 60 sidechain, the Trp 59 sidechain, and of the structurally interposed α-helix hydrogen bonding pattern yielded a statistical allosteric coupling of 10 kJ/mol with negligible concerted dynamical coupling for the transitions of the two sidechains.
authors.affiliation: Department of Chemistry, Union College, Schenectady, NY 12308, United States.
authors.forename: Janet S
authors.initials: JS
authors.lastname: Anderson
authors.affiliation: Wadsworth Center, New York State Department of Health, Empire State Plaza, Albany, NY 12201, United States.
authors.forename: Sourajit M
authors.initials: SM
authors.lastname: Mustafi
authors.affiliation: Wadsworth Center, New York State Department of Health, Empire State Plaza, Albany, NY 12201, United States; Department of Biomedical Sciences, School of Public Health, University at Albany - SUNY, Empire State Plaza, Albany, NY 12201, United States.
authors.forename: Griselda
authors.initials: G
authors.lastname: Hernández
authors.affiliation: Wadsworth Center, New York State Department of Health, Empire State Plaza, Albany, NY 12201, United States; Department of Biomedical Sciences, School of Public Health, University at Albany - SUNY, Empire State Plaza, Albany, NY 12201, United States. Electronic address: david.lemaster@health.ny.gov.
authors.forename: David M
authors.initials: DM
authors.lastname: LeMaster
mesh_terms: D020134:Catalytic Domain; D003627:Data Interpretation, Statistical; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D017434:Protein Structure, Tertiary; D016559:Tacrolimus / Q000737:chemistry*; D022061:Tacrolimus Binding Protein 1A / Q000737:chemistry*; D022021:Tacrolimus Binding Proteins / Q000737:chemistry; D000099159:Tacrolimus Binding Protein 5
chemical_list: D007211:Indoles; D016559:Tacrolimus; D022061:Tacrolimus Binding Protein 1A; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C030374:indole
keywords: Allostery; Concerted transition; FKBP12; Molecular simulation; NMR; Statistical coupling