title: Free energy landscape of activation in a signalling protein at atomic resolution.
abstract: The interconversion between inactive and active protein states, traditionally described by two static structures, is at the heart of signalling. However, how folded states interconvert is largely unknown due to the inability to experimentally observe transition pathways. Here we explore the free energy landscape of the bacterial response regulator NtrC by combining computation and nuclear magnetic resonance, and discover unexpected features underlying efficient signalling. We find that functional states are defined purely in kinetic and not structural terms. The need of a well-defined conformer, crucial to the active state, is absent in the inactive state, which comprises a heterogeneous collection of conformers. The transition between active and inactive states occurs through multiple pathways, facilitated by a number of nonnative transient hydrogen bonds, thus lowering the transition barrier through both entropic and enthalpic contributions. These findings may represent general features for functional conformational transitions within the folded state.
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02452, USA.
authors.forename: F
authors.initials: F
authors.lastname: Pontiggia
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02452, USA.
authors.forename: D V
authors.initials: DV
authors.lastname: Pachov
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02452, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Clarkson
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02452, USA.
authors.forename: J
authors.initials: J
authors.lastname: Villali
authors.affiliation: Department of Physics, Brandeis University, Waltham, Massachusetts 02452, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Hagan
authors.affiliation: Department of Chemistry and SIMBIOS, NIH Center for Biomedical Computation, Department of Bioengineering, Stanford University, Stanford, California 94305, USA.
authors.forename: V S
authors.initials: VS
authors.lastname: Pande
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02452, USA.
authors.forename: D
authors.initials: D
authors.lastname: Kern
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D019277:Entropy; D006860:Hydrogen Bonding; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008390:Markov Chains; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D051922:PII Nitrogen Regulatory Proteins / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013816:Thermodynamics
chemical_list: D001426:Bacterial Proteins; D051922:PII Nitrogen Regulatory Proteins