New methods for computational drug design

This thesis describes the work that has been carried out in connection with my Masters at the University of Copenhagen. This work has led to new dispersion and hydrogen bond corrections to the PM6 method, PM6-D3H+, and its implementation in the GAMESS program. The method combines the DFT-D3 dispersion correction by Grimme et al. with a modified version of the H+ hydrogen bond correction by Korth. This work also included the implementation of the new HF-3c method in GAMESS and its interface with the fragmentation method FMO. Overall, the interaction energy of PM6-D3H+ is very similar to PM6-DH2 and PM6-DH+, with RMSD and MAD values within 0.02 kcal/mol of one another. HF-3c also shows interaction energies within the same order of accuracy as the PM6 based methods. The main difference is that the geometry optimizations of 88 complexes result in 82, 6, 0, and 0 geometries with 0, 1, 2, and 3 or more imaginary frequencies using PM6-D3H+ implemented in GAMESS, while the corresponding numbers for PM6-DH+ implemented in MOPAC are 54, 17, 15, and 2. PM6-D3H+ and FMO2-HF- 3c in GAMESS was used to optimize two small proteins which resulted in a much more reliable structure compared to the reference structures, than PM6-DH+ in MOPAC, most likely due to the different optimization algorithms associated with the programs. The PM6-D3H+ method as implemented in GAMESS offers an attractive alternative to PM6-DH+ in MOPAC in cases where the LBFGS optimizer must be used and a vibrational analysis is needed, e.g., when computing vibrational free energies. While the GAMESS implementation is up to 10 times slower for geometry optimizations of proteins in bulk solvent compared to MOPAC, it is sufficiently fast to make geometry optimizations of small proteins practically feasible.