In this dissertation computational chemistry methods were applied to study the properties of prenyltransferase FtmPT1 and small ligand conformational changes. First, I have done thorough investigations on FtmPT1 enzyme catalysis by the quantum mechanics and molecular mechanics method. FtmPT1 is a fungal indole prenyltransferase that catalyzes the reaction of tryptophan derivatives with dimethylallyl pyrophosphate to form various biologically active compounds. Herein I describe detailed studies of FtmPT1 catalysis involving dimethylallyl pyrophosphate and Brevianamide F following the native pathway (yielding Tryprostatin B) and an alternate pathway observed in the Gly115Thr mutant of FtmPT1, yielding a novel cyclized product. Importantly, these two products arise from the same intermediate state, meaning that a step other than the cleavage of the dimethylallyl pyrophosphate (DMAPP; C-O) bond is differentiating between the two product reaction channels. From detailed potential of mean force (PMF) and 2-D PMF analyses I conclude that the rate-limiting step is the cleavage of the C-O bond in DMAPP, while the deprotonation/cyclization step determines the final product distribution. Hence, in the case of FtmPT1, the optimization of the necessary catalytic machinery guides the generation of the final product after the intermediate carbocation formation.I also describe a conformational search algorithm using the “Movable Type” (MT) sampling method. Differing from traditional systematic and stochastic searching algorithms, this method uses probability information to facilitate the selection of the best conformations. The generated ensembles provided good coverage of the available conformation space including available crystal structures. Furthermore, my approach directly provides the solvation free energies and the relative gas and aqueous phase free energies for all generated conformers. The method was validated against thorough analyses on thrombin ligands as well as against structures extracted from both the Protein Data Bank (PDB) and the Cambridge Structural Database (CSD). These studies demonstrate that this MT-based ligand conformational search algorithm is a powerful approach for delineating the conformer ensembles of molecular species.
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