Molecular dynamics simulation studies of DNA and proteins: Force field parameter development for small ligands and convergence analysis for simulations of biomolecules.

摘要

In the first part of this dissertation, CHARMM force field parameters for DNA minor groove-binding polyamides were developed. The parameterization involved the subdivision of the polyamides into model compounds, which were calibrated against MP2/6-31G(d) data. To test the new parameters, fourteen 10 ns molecular dynamics crystal simulations have been carried out on a DNA/polyamide complex at low (113K) and high (300K) temperatures. Of the 18 helical parameters examined, only one (stagger) is found to be statistically significant from the crystal structure with a t-test at the 95% confidence level. For the high temperature, stagger is non-significant at the 97% confidence level, which underscores the importance of running multiple trajectories. It is observed that when the simulations are run at 300K, the DNA fragment begins to distort; however, better sampling is achieved. Competition between water and polyamides for hydrogen bonding to DNA is found to explain weak or unpredictable binding.; In the second part, force field parameters for retinoids were developed. The retinoids were divided into model compounds and calibrated against MP2/6-31G(d) data. To test the parameters, five molecular dynamics crystal simulations of reported x-ray structures of protein/retinoid complexes were performed. The structural and geometric analysis of these simulations compares well to experiment, and some dynamics that could be important to ligand binding were discovered. The new parameters can now be used in simulations of retinoid-binding proteins to better understand these systems and in drug design to make new retinoids with therapeutic and anticancer potential.; The last part explores the convergence of structural parameters in biomolecular systems. A simple statistical test was applied to the different parameters from a few long and many short simulations to observe which strategy is best. For the protein, both the long and short simulations gave similar results with respect to convergence. For the DNA, it was found that fraying effects penetrate four base pairs in from the ends of the helix. Structural parameters converge more quickly for the middle four bases than for all bases, and the long simulations yielded better results with respect to convergence than the short simulations.