title: Chemomechanical Coupling in Hexameric Protein-Protein Interfaces Harnesses Energy within V-Type ATPases.
abstract: ATP synthase is the most prominent bioenergetic macromolecular motor in all life forms, utilizing the proton gradient across the cell membrane to fuel the synthesis of ATP. Notwithstanding the wealth of available biochemical and structural information inferred from years of experiments, the precise molecular mechanism whereby vacuolar (V-type) ATP synthase fulfills its biological function remains largely fragmentary. Recently, crystallographers provided the first high-resolution view of ATP activity in Enterococcus hirae V1-ATPase. Employing a combination of transition-path sampling and high-performance free-energy methods, the sequence of conformational transitions involved in a functional cycle accompanying ATP hydrolysis has been investigated in unprecedented detail over an aggregate simulation time of 65 μs. Our simulated pathways reveal that the chemical energy produced by ATP hydrolysis is harnessed via the concerted motion of the protein-protein interfaces in the V1-ring, and is nearly entirely consumed in the rotation of the central stalk. Surprisingly, in an ATPase devoid of a central stalk, the interfaces of this ring are perfectly designed for inducing ATP hydrolysis. However, in a complete V1-ATPase, the mechanical property of the central stalk is a key determinant of the rate of ATP turnover. The simulations further unveil a sequence of events, whereby unbinding of the hydrolysis product (ADP + Pi) is followed by ATP uptake, which, in turn, leads to the torque generation step and rotation of the center stalk. Molecular trajectories also bring to light multiple intermediates, two of which have been isolated in independent crystallography experiments.
authors.affiliation: Theoretical and Computational Biophysics Group, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign , 405 North Mathews Avenue, Urbana, Illinois 61801, United States.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Singharoy
authors.affiliation: Theoretical and Computational Biophysics Group, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign , 405 North Mathews Avenue, Urbana, Illinois 61801, United States.|Laboratoire International Associé Centre National de la Recherche Scientifique et University of Illinois at Urbana-Champaign, Unité Mixte de Recherche n°7565, Université de Lorraine , B.P. 70239, 54506 Vandœuvre-lès-Nancy Cedex, France.|Department of Physics, University of Illinois at Urbana-Champaign , 1110 West Green Street, Urbana, Illinois 61801, United States.
authors.forename: Christophe
authors.identifier: 0000-0002-9122-1698
authors.initials: C
authors.lastname: Chipot
authors.affiliation: Department of Chemistry and Biochemistry, University of Arkansas , Fayetteville, Arkansas 72701, United States.
authors.forename: Mahmoud
authors.identifier: 0000-0002-0601-402X
authors.initials: M
authors.lastname: Moradi
authors.affiliation: Theoretical and Computational Biophysics Group, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign , 405 North Mathews Avenue, Urbana, Illinois 61801, United States.|Department of Physics, University of Illinois at Urbana-Champaign , 1110 West Green Street, Urbana, Illinois 61801, United States.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulten
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism*; D000070076:Enterococcus hirae / Q000201:enzymology; D006868:Hydrolysis; D008958:Models, Molecular; D011485:Protein Binding; D025262:Vacuolar Proton-Translocating ATPases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000255:Adenosine Triphosphate; D025262:Vacuolar Proton-Translocating ATPases