Atomistic simulations of competition between substrates binding to an enzyme

Adrian H Elcock

doi:10.1016/S0006-3495(02)75578-1

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Atomistic simulations of competition between substrates binding to an enzyme

Journal article

Open access

Peer reviewed

Atomistic simulations of competition between substrates binding to an enzyme

Adrian H Elcock

Biophysical journal, Vol.82(5), pp.2326-2332

05/2002

DOI: 10.1016/S0006-3495(02)75578-1

PMCID: PMC1302025

PMID: 11964223

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Abstract

Although the idea that electrostatic potentials generated by enzymes can guide substrates to active sites is well established, it is not always appreciated that the same potentials can also promote the binding of molecules other than the intended substrate, with the result that such enzymes might be sensitive to the presence of competing molecules. To provide a novel means of studying such "electrostatic competition" effects, computer simulation methodology has been developed to allow the diffusion and association of many solute molecules around a single enzyme to be simulated. To demonstrate the power of the methodology, simulations have been conducted on an artificial fusion protein of citrate synthase (CS) and malate dehydrogenase (MDH) to assess the chances of oxaloacetate being channeled between the MDH and CS active sites. The simulations demonstrate that the probability of channeling is strongly dependent on the concentration of the initial substrate (malate) in the solution. In fact, the high concentrations of malate used in experiments appear high enough to abolish any channeling of oxaloacetate. The simulations provide a resolution of a serious discrepancy between previous simulations and experiments and raise important questions relating to the observability of electrostatically mediated substrate channeling in vitro and in vivo.

Enzymes - chemistry

Models, Theoretical

Models, Molecular

Substrate Specificity

Recombinant Fusion Proteins - chemistry

Static Electricity

Recombinant Fusion Proteins - metabolism

Malates - chemistry

Osmolar Concentration

Computer Simulation

Protein Conformation

Citrate (si)-Synthase - metabolism

Citrate (si)-Synthase - chemistry

Kinetics

Binding Sites

Enzymes - metabolism

Details

Title: Subtitle: Atomistic simulations of competition between substrates binding to an enzyme
Creators: Adrian H Elcock - Department of Biochemistry, University of Iowa, Iowa City, Iowa 55242, USA. adrian-elcock@uiowa.edu
Resource Type: Journal article
Publication Details: Biophysical journal, Vol.82(5), pp.2326-2332
Publisher: United States
DOI: 10.1016/S0006-3495(02)75578-1
PMID: 11964223
PMCID: PMC1302025
ISSN: 0006-3495
eISSN: 1542-0086
Language: English
Date published: 05/2002
Academic Unit: Physics and Astronomy; Biochemistry and Molecular Biology
Record Identifier: 9984024405402771

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