UC San Diego

Molecular dynamics are increasingly used to construct conformational ensembles of biochemical systems. The accuracy of these ensembles is determined by the accuracy of the underlying model and the extent of conformational sampling during the simulation. Biochemical systems can have motion on time scales that vary by several orders of magnitude, and these must all be described before a specific model can be validated. For this reason research into enhanced sampling methods that accelerate conformational sampling are vital to the progress of molecular dynamics. This dissertation describes the validation and application of the replica exchange accelerated molecular dynamics (REXAMD) method in the context of free energy calculations. In chapters 2 and 3 the REXAMD method is validated using simple model systems. The convergence of REXAMD is shown to be an improvement over classical molecular dynamics. Additionally, various methods to improve the statistical behavior of REXAMD are investigated. In chapter 4 gradient-augmented Harmonic Fourier Beads, a minimum free energy pathway method, is used to study the conformational change of the ion selectivity peptide from the KcsA potassium channel. The robustness of various models, ranging from classical to quantum mechanical, is investigated and the importance of conformational sampling is observed. Finally in chapter 5, I propose a modification to the AMBER molecular dynamics package which allows the calculation of absolute binding free energies to be computed