An unconventional ligand-binding mechanism of substrate-binding proteins: MD simulation and Markov state model analysis of BtuF |
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Authors: | Dongdong Wang Jingwei Weng Wenning Wang |
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Institution: | Department of Chemistry, Institutes of Biomedical Sciences and Multiscale Research Institute of Complex System, Fudan University, Shanghai 200438, People's Republic of China |
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Abstract: | In conventional “Venus Flytrap” mechanism, substrate-binding proteins (SBPs) interconvert between the open and closed conformations. Upon ligand binding, SBPs form a tightly closed conformation with the ligand bound at the interface of two domains. This mechanism was later challenged by many type III SBPs, such as the vitamin B12-binding protein BtuF, in which the apo- and holo-state proteins adopt very similar conformations. Here, we combined molecular dynamics simulation and Markov state model analysis to study the conformational dynamics of apo- and B12-bound BtuF. The results indicate that the crystal structures represent the only stable conformation of BtuF. Meanwhile, both apo- and holo-BtuF undergo large-scale interdomain motions with little energy cost. B12 binding casts little restraints on the interdomain motions, suggesting that ligand binding affinity is enhanced by the remaining conformational entropy of holo-BtuF. These results reveal a new paradigm of ligand recognition mechanism of SBPs. © 2019 Wiley Periodicals, Inc. |
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Keywords: | periplasmic binding protein MD simulation Markov state model conformational dynamics intrinsic disorder |
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