Journal of Computational Chemistry | 2019
An unconventional ligand‐binding mechanism of substrate‐binding proteins: MD simulation and Markov state model analysis of BtuF
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.