Clostridium difficile (C. diff) is an opportunistic pathogen that can cause potentially lethal hospital-acquired disease. The cellular damage that it causes is the result of two large clostridial cytotoxins: TcdA and TcdB. As C. diff is highly antibiotic resistant, anti-toxin therapies may prove useful.  While TcdB is a large flexible protein, the only available structural information about the catalytic domain is a single crystal structure. To fully characterize conformational space of TcdB, we applied normal mode and hinge-region analysis, followed by long-timescale unbiased molecular dynamics. In order to examine the TcdB and RhoA interaction, macromolecular docking and simulation of the TcdB/RhoA complex was performed.  GMD analysis of the simulations determined the extent of significant motions. This combination of methods elucidated the wide range of motions TcdB is capable of, as well as providing a look at the range of active site conformations TcdB uses to recognize its substrates.

Computational investigations into the flexibility and molecular motions of <i>Clostridium difficle </i>Toxin B

243rd National Meeting (2012)

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Computational investigations into the flexibility and molecular motions of Clostridium difficle Toxin B