Replica exchange simulations of transient encounter complexes in protein-protein association.

Replica exchange simulations of transient encounter complexes in protein-protein association. Research Abstract Details 

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Replica exchange simulations of transient encounter complexes in protein-protein association. Abstract Text:

Recent paramagnetic relaxation enhancement (PRE) studies on several weakly interacting protein complexes have unequivocally demonstrated the existence of transient encounter complexes. Here, we present a computational method to study protein-protein binding by creating equilibrium ensembles that include both specific and nonspecific protein complexes. In a joint analysis of simulation and experiment we explore the physical nature and underlying physicochemical characteristics of encounter complexes involving three protein-protein interactions of the bacterial phosphotransferase system. Replica exchange Monte Carlo simulations using a coarse-grained energy function recover the structures of the specific complexes and produce binding affinities in good agreement with experiment. Together with the specific complex, a relatively small number of distinct nonspecific complexes largely accounts for the measured PRE data. The combined relative population of the latter is less than approximately 10%. The binding interfaces of the specific and nonspecific complexes differ primarily in size but exhibit similar amino acid compositions. We find that the overall funnel-shaped energy landscape of complex formation is dominated by the specific complex, a small number of structured nonspecific complexes, and a diffuse cloud of loosely bound complexes connecting the specific and nonspecific binding sites with each other and the unbound state. Nonspecific complexes may not only accelerate the binding kinetics by enhancing the rate of success of random diffusional encounters but also play a role in protein function as alternative binding modes.

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Replica exchange simulations of transient encounter complexes in protein-protein association. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Proceedings of the National Academy of Sciences of

VOLUME: 105

Page Numbers: 12855-60

Journal Abbreviation: Proc. Natl. Acad. Sci. U.S.A.

ISSN: 1091-6490

DAY: 26

MONTH: 08

YEAR: 2008

Replica exchange simulations of transient encounter complexes in protein-protein association. Information

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LANGUAGE: eng

NlmUniqueID: 7505876

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Grant and Affiliation Information for Replica exchange simulations of transient encounter complexes in protein-protein association.

AFFILIATION: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520.

Country: United States

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MEDLINETA: Proc Natl Acad Sci U S A

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