文章基本信息

标题：Replica exchange simulations of transient encounter complexes in protein–protein association
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作者：Young C. Kim ; Chun Tang ; G. Marius Clore 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2008
卷号：105
期号：35
页码：12855-12860
DOI：10.1073/pnas.0802460105
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 [~]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.
关键词：protein binding ; transient nonspecific encounter complexes ; paramagnetic relaxation enhancement ; bacterial phosphotransferase system