How Intrinsic Dynamics Mediates the Allosteric Mechanism in the ABC Transporter Nucleotide Binding Domain Dimer

Jones, PM; George, AM

How Intrinsic Dynamics Mediates the Allosteric Mechanism in the ABC Transporter Nucleotide Binding Domain Dimer

Jones, PM George, AM

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Publication Type:: Journal Article
Citation:: Journal of Chemical Theory and Computation, 2017, 13 (4), pp. 1712 - 1722
Issue Date:: 2017-04-11

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Field	Value	Language
dc.contributor.author	Jones, PM	en_US
dc.contributor.author	George, AM https://orcid.org/0000-0003-4691-8960	en_US
dc.date.issued	2017-04-11	en_US
dc.identifier.citation	Journal of Chemical Theory and Computation, 2017, 13 (4), pp. 1712 - 1722	en_US
dc.identifier.issn	1549-9618	en_US
dc.identifier.uri	http://hdl.handle.net/10453/124887
dc.description.abstract	© 2017 American Chemical Society. A protein's architecture facilitates specific motions - intrinsic dynamic modes - that are employed to effect function. Here we used molecular dynamics (MD) simulations to investigate the dynamics of the MJ0796 ABC transporter nucleotide-binding domain (NBD). ABC transporter NBDs form a rotationally symmetric dimer whereby two equivalent active sites are formed at their interface; in complex with a dimer of transmembrane domains they hydrolyze ATP to energize translocation of substrates across cellular membranes. Our data suggest the ABC NBD's ensemble of functional states can be understood predominately in terms of conformational changes between its major subdomains, occurring along two orthogonal dynamic modes. The data show that ligands and oligomeric interactions modulate the equilibrium conformation of the NBD with respect to these motions, suggesting that allostery is achieved by affecting the energetic profile along these two modes. The observed dynamics and allostery integrate consonantly and logically within a mechanistic framework for the ABC NBD dimer, which is supported by a large body of experimental and theoretical data, providing a higher resolution view of the enzyme's dynamic cycle. Our study shows how valuable mechanistic inferences can be derived from accessible short-time scale MD simulations of an enzyme's substructures.	en_US
dc.relation.ispartof	Journal of Chemical Theory and Computation	en_US
dc.relation.isbasedon	10.1021/acs.jctc.6b00839	en_US
dc.subject.classification	Chemical Physics	en_US
dc.subject.mesh	Nucleotides	en_US
dc.subject.mesh	ATP-Binding Cassette Transporters	en_US
dc.subject.mesh	Allosteric Regulation	en_US
dc.subject.mesh	Molecular Conformation	en_US
dc.subject.mesh	Molecular Dynamics Simulation	en_US
dc.title	How Intrinsic Dynamics Mediates the Allosteric Mechanism in the ABC Transporter Nucleotide Binding Domain Dimer	en_US
dc.type	Journal Article
utslib.citation.volume	4	en_US
utslib.citation.volume	13	en_US
utslib.for	0307 Theoretical and Computational Chemistry	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
utslib.for	0803 Computer Software	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	closed_access
pubs.issue	4	en_US
pubs.publication-status	Published	en_US
pubs.volume	13	en_US

Abstract:

© 2017 American Chemical Society. A protein's architecture facilitates specific motions - intrinsic dynamic modes - that are employed to effect function. Here we used molecular dynamics (MD) simulations to investigate the dynamics of the MJ0796 ABC transporter nucleotide-binding domain (NBD). ABC transporter NBDs form a rotationally symmetric dimer whereby two equivalent active sites are formed at their interface; in complex with a dimer of transmembrane domains they hydrolyze ATP to energize translocation of substrates across cellular membranes. Our data suggest the ABC NBD's ensemble of functional states can be understood predominately in terms of conformational changes between its major subdomains, occurring along two orthogonal dynamic modes. The data show that ligands and oligomeric interactions modulate the equilibrium conformation of the NBD with respect to these motions, suggesting that allostery is achieved by affecting the energetic profile along these two modes. The observed dynamics and allostery integrate consonantly and logically within a mechanistic framework for the ABC NBD dimer, which is supported by a large body of experimental and theoretical data, providing a higher resolution view of the enzyme's dynamic cycle. Our study shows how valuable mechanistic inferences can be derived from accessible short-time scale MD simulations of an enzyme's substructures.

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http://hdl.handle.net/10453/124887