Joined University of Redlands Faculty, 2020
Joined Wyzant Chemistry Tutoring, 2013
Joined Vanguard University Faculty, 2012
Dox Research Fellowship, Yale University, 2009
Distinguished Chemistry Fellowship, Yale University, 2006-2011
Robert D. Engel Award, University of Redlands, 2006
Edmund C. Jaeger Award, University of Redlands, 2005
My research projects use computers to explore questions in modern chemistry that experimental methods often cannot answer. Specifically, we apply chemical theory, statistics, and informatics to study the relationship between the structure of organic molecules and their activity in biological systems. This "quantitative structure-activity relationship," or QSAR, allows us to design molecules with certain desired pharmacological properties, with the ultimate goal of developing therapeutic agents targeting infectious, inflammatory, and hyperproliferative diseases.
In my dissertation, an implementation of the generalized Born / surface area (GB/SA) solvation model with free-energy perturbation (FEP), including an approximation used in calculating the total Born energy of the system, is presented. Our approximation is based on the assumption that a significant number of pairwise energy calculations may be omitted with little-to-no impact on the total change in energy of the system after a Monte Carlo move because the impact of a moving atom on the Born radius of a distant atom is small. Thus, we structured our implementation of GB/SA in such a way that the Born energy between an unmoving pair of atoms is only recalculated after a move if the Born radius of either atom has changed by more than a specified threshold since the last accepted move. Prior benchmarks demonstrated that existing GB/SA methodologies were insufficient for the purposes of calculating free energies of binding, and FEP simulations with GB/SA solvation were too computationally expensive to be used with any practicality. With our approximation, improved efficiency was achieved while affording minimal error: the influence of our approximation on accuracy of free energies of binding was negligible, with any error introduced by the approximation falling well below the statistical error of the Metropolis Monte Carlo algorithm, and speed-up of up to 62% was observed. The conclusion is that with our approximation, GB/SA is a viable solvent choice for FEP of large systems. Comparison between GB/SA and TIP4P in a substituent scan was quantitative to qualitative, with free energies of binding usually in agreement within 1 kcal/mol, producing the same substitution pattern on a drug candidate found to give high anti-retroviral activity as predicted by previous simulations with TIP4P explicit water.
Thermochemical data obtained from G3B3 quantum mechanical calculations are presented for 18 prototypical organic molecules that exhibit E/Z conformational equilibria. The results are fundamentally important for molecular design including the evaluation of structures from protein--ligand docking. For the 18 E/Z pairs, relative energies, enthalpies, free energies, and dipole moments are reported; the E-Z free-energy differences at 298 K range from +8.2 kcal/mol for 1,3-dimethyl carbamate to -6.4 kcal/mol for acetone oxime. A combination of steric and electronic effects can rationalize the variations. Free energies of hydration were also estimated using the GB/SA continuum solvent model. These results indicate that differential hydration is unlikely to qualitatively change the preferred direction of the E/Z equilibria.
E/Z Energetics for Molecular Modeling and Design.
J. Terhorst and W. L. Jorgensen
J. Chem. Theory Comput. 2010, 6:9, 2762-2769. doi:10.1021/ct1004017
Simulations of Photopumping in Doubly Illuminated Liquid Membranes Containing Photoactive Carriers.
T. L. Longin, J. Terhorst, and C. Lang
J. Phys. Chem. B 2010, 114:48 15846-15858. doi:10.1021/jp106802q
Complete Vita (pdf) | Links
Last updated: 2023-03-29 05:33 GMT