Random search conformational analysis of piperazine and piperadine analogs of GBR12909 : Implicit aqueous solvation effects
College of Computing Sciences
Master of Science
Venanzi, Carol A.
Gund, Tamara M.
Conformational potential energy surface
The object of this work was to study the effect of solvent on the conformational potential energy surface (PES) of GBR12909 analogs. Local minima on the PES's were found by the Random Search algorithm using the Sybyl molecular modeling package from Tripos, Inc., and an implicit solvent model. Two force-field/charge models were employed in the analysis: the Tripos force field with Gasteiger-Huckel charges and the MMFF94 force field with MMFF94 charges.
The effect of solvent on the location of minima in multi-dimensional torsional angle space was studied by comparison to the vacuum phase results. Minima were plotted in torsional angle space using successive pairs of torsional angles. The results showed that, at least for the simple implicit solvent model used here, solvation does not significantly affect the location of the conformational minima for either of the two analogs investigated. With the MMIFF94 model, some of the conformational energy minima were found in a narrower range of torsional angle space in the solvent compared to the vacuum phase, while there were no consistent differences with the Tripos model. One notable exception was the Tripos solvent phase results for the piperadine analog where a cluster of minima was found in a region of torsional angle space where no minima were present in the original vacuum phase results. This is believed to be an anomaly arising from incomplete searching of the conformational PES of the molecule. This was supported by the results of a second vacuum phase random search, which were similar to those of the solvation case. Further study remains to be performed employing other more sophisticated solvation models and conformational search techniques.
njit-etd2004-068 (206 pages ~ 28,444 KB pdf)
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Created November 3, 2004