COMP 401 |
| N-acyl-L-homoserine lactones (AHL's) are believed to be involved in cell-to-cell communication, regulating gene expression and group behavior in bacteria. This phenomenon is also referred to as quorum sensing (QS); thus, quorum-quenching proteins, such as AHL-Lactonases constitute an appealing new target for therapeutic approaches to control pathogens. Based on the recent crystal structure of the inhibitor-enzyme complex of AHL-lactonase of Bacillus thuringiensis at 1.7 Å (1), we apply an extensive multi-step computational investigation with the scope to rationalize the structure-activity data for real substrates and, hence, better understand the mechanism of AHL-Lactonases. A standard docking procedure is applied to identify possible substrate binding modes followed by the modeling of a mobile loop region, not defined in the experimental structure. Then, classical molecular dynamics simulations have been performed in order to further refine the best docked structures and to equilibrate the solvated system. Finally, we discriminate among possible binding modes by looking at the enzymatic reaction energy profiles and comparing them to experimental data. To this aim, Car-Parrinello QM/MM simulations together with an Umbrella-sampling scheme are performed. We confront our findings to the reaction mechanism of other members of the metallo-β-lactamase folding family (e.g. CcrA from Bacteroides fragilis, and Glyoxalase II). (1) Kim M.H., Choi W.-C., Kang H.O., Lee J.S., Kang B.S., Kim K.-J., Derewenda Z.S., Oh T.-K., Lee C.H., Lee J.-K. PNAS, 102(49):17606-17611 (2005). |
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Free Energy Computations in Drug Discovery
1:00 PM-6:00 PM, Thursday, 14 September 2006 Moscone Center -- Room 220/222, Oral
Division of Computers in Chemistry |