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

Proceedings of the National Academy of Sciences of the United States of America
Young C KimGerhard Hummer

Abstract

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...Continue Reading

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Citations

Aug 3, 2010·Journal of the American Chemical Society·Alexander N VolkovMarcellus Ubbink
May 9, 2012·Journal of the American Chemical Society·Kei-ichi OkazakiMitsunori Takano
Nov 19, 2009·Journal of the American Chemical Society·Agnes Tóth-PetróczyYaakov Levy
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