title: Dynamic allostery governs cyclophilin A-HIV capsid interplay.
abstract: Host factor protein Cyclophilin A (CypA) regulates HIV-1 viral infectivity through direct interactions with the viral capsid, by an unknown mechanism. CypA can either promote or inhibit viral infection, depending on host cell type and HIV-1 capsid (CA) protein sequence. We have examined the role of conformational dynamics on the nanosecond to millisecond timescale in HIV-1 CA assemblies in the escape from CypA dependence, by magic-angle spinning (MAS) NMR and molecular dynamics (MD). Through the analysis of backbone (1)H-(15)N and (1)H-(13)C dipolar tensors and peak intensities from 3D MAS NMR spectra of wild-type and the A92E and G94D CypA escape mutants, we demonstrate that assembled CA is dynamic, particularly in loop regions. The CypA loop in assembled wild-type CA from two strains exhibits unprecedented mobility on the nanosecond to microsecond timescales, and the experimental NMR dipolar order parameters are in quantitative agreement with those calculated from MD trajectories. Remarkably, the CypA loop dynamics of wild-type CA HXB2 assembly is significantly attenuated upon CypA binding, and the dynamics profiles of the A92E and G94D CypA escape mutants closely resemble that of wild-type CA assembly in complex with CypA. These results suggest that CypA loop dynamics is a determining factor in HIV-1's escape from CypA dependence.
authors.affiliation: Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716; Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260;
authors.forename: Manman
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716; Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260;
authors.forename: Guangjin
authors.initials: G
authors.lastname: Hou
authors.affiliation: Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716; Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260;
authors.forename: Huilan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716; Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260;
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Suiter
authors.affiliation: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260; Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260;
authors.forename: Jinwoo
authors.initials: J
authors.lastname: Ahn
authors.affiliation: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260; Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260;
authors.forename: In-Ja L
authors.initials: IJ
authors.lastname: Byeon
authors.affiliation: Center for Biophysics and Computational Biology and Beckman Institute for Advanced Science and Technology and Departments of Physics, Chemistry, and Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: Juan R
authors.identifier: http://orcid.org/0000-0003-1171-6816
authors.initials: JR
authors.lastname: Perilla
authors.affiliation: School of Computer Science, Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213;
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Langmead
authors.affiliation: National High Magnetic Field Laboratory, Florida State University, Tallahassee, FL 32310;
authors.forename: Ivan
authors.initials: I
authors.lastname: Hung
authors.affiliation: National High Magnetic Field Laboratory, Florida State University, Tallahassee, FL 32310;
authors.forename: Peter L
authors.initials: PL
authors.lastname: Gor'kov
authors.affiliation: National High Magnetic Field Laboratory, Florida State University, Tallahassee, FL 32310;
authors.forename: Zhehong
authors.initials: Z
authors.lastname: Gan
authors.affiliation: National High Magnetic Field Laboratory, Florida State University, Tallahassee, FL 32310;
authors.forename: William
authors.initials: W
authors.lastname: Brey
authors.affiliation: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260; Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors.forename: Christopher
authors.initials: C
authors.lastname: Aiken
authors.affiliation: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260; Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260;
authors.forename: Peijun
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Center for Biophysics and Computational Biology and Beckman Institute for Advanced Science and Technology and Departments of Physics, Chemistry, and Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulten
authors.affiliation: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260; Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260; tpolenov@udel.edu amg100@pitt.edu.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Gronenborn
authors.affiliation: Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716; Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260; tpolenov@udel.edu amg100@pitt.edu.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Polenova
mesh_terms: D000494:Allosteric Regulation; D002213:Capsid / Q000737:chemistry* / Q000648:ultrastructure; D021984:Cyclophilin A / Q000737:chemistry* / Q000648:ultrastructure; D015497:HIV-1 / Q000737:chemistry* / Q000648:ultrastructure; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D050505:Mutant Proteins / Q000737:chemistry; D009154:Mutation / Q000235:genetics; D013997:Time Factors
chemical_list: D050505:Mutant Proteins; D021984:Cyclophilin A
keywords: CA protein assemblies; HIV-1 capsid; conformational dynamics; escape mutations; magic angle spinning NMR