Absolute protein-protein association rate constants from flexible, coarse-grained Brownian dynamics simulations: the role of intermolecular hydrodynamic interactions in barnase-barstar association

Tamara Frembgen-Kesner; Adrian H Elcock

doi:10.1016/j.bpj.2010.09.006

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Absolute protein-protein association rate constants from flexible, coarse-grained Brownian dynamics simulations: the role of intermolecular hydrodynamic interactions in barnase-barstar association

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Absolute protein-protein association rate constants from flexible, coarse-grained Brownian dynamics simulations: the role of intermolecular hydrodynamic interactions in barnase-barstar association

Tamara Frembgen-Kesner and Adrian H Elcock

Biophysical journal, Vol.99(9), pp.L75-L77

11/03/2010

DOI: 10.1016/j.bpj.2010.09.006

PMCID: PMC2965997

PMID: 21044566

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Abstract

Theory and computation have long been used to rationalize the experimental association rate constants of protein-protein complexes, and Brownian dynamics (BD) simulations, in particular, have been successful in reproducing the relative rate constants of wild-type and mutant protein pairs. Missing from previous BD studies of association kinetics, however, has been the description of hydrodynamic interactions (HIs) between, and within, the diffusing proteins. Here we address this issue by rigorously including HIs in BD simulations of the barnase-barstar association reaction. We first show that even very simplified representations of the proteins--involving approximately one pseudoatom for every three residues in the protein--can provide excellent reproduction of the absolute association rate constants of wild-type and mutant protein pairs. We then show that simulations that include intermolecular HIs also produce excellent estimates of association rate constants, but, for a given reaction criterion, yield values that are decreased by ∼35-80% relative to those obtained in the absence of intermolecular HIs. The neglect of intermolecular HIs in previous BD simulation studies, therefore, is likely to have contributed to the somewhat overestimated absolute rate constants previously obtained. Consequently, intermolecular HIs could be an important component to include in accurate modeling of the kinetics of macromolecular association events.

Ribonucleases - genetics

Biophysical Phenomena

Mutagenesis, Site-Directed

Ribonucleases - chemistry

Bacterial Proteins - chemistry

Bacterial Proteins - genetics

Mutant Proteins - genetics

Models, Molecular

Hydrodynamics

Mutant Proteins - metabolism

Molecular Dynamics Simulation

Ribonucleases - metabolism

Multiprotein Complexes - metabolism

Multiprotein Complexes - chemistry

Mutant Proteins - chemistry

Bacterial Proteins - metabolism

Protein Interaction Domains and Motifs

Kinetics

Amino Acid Substitution

Details

Title: Subtitle: Absolute protein-protein association rate constants from flexible, coarse-grained Brownian dynamics simulations: the role of intermolecular hydrodynamic interactions in barnase-barstar association
Creators: Tamara Frembgen-Kesner - Department of Biochemistry, University of Iowa, Iowa City, Iowa, USA
Adrian H Elcock
Resource Type: Journal article
Publication Details: Biophysical journal, Vol.99(9), pp.L75-L77
Publisher: United States
DOI: 10.1016/j.bpj.2010.09.006
PMID: 21044566
PMCID: PMC2965997
ISSN: 0006-3495
eISSN: 1542-0086
Grant note: R01 GM087290 / NIGMS NIH HHS GM087290 / NIGMS NIH HHS
Language: English
Date published: 11/03/2010
Academic Unit: Physics and Astronomy; Biochemistry and Molecular Biology
Record Identifier: 9984025394502771

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