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Improvements and Applications of Alchemical Free Energy, Constant pH and Accelerated Molecular Dynamics Calculations in the AMBER Molecular Dynamics Suite.


The field of molecular dynamics is rapidly advancing as new theoretical techniques, software optimizations and computer architectures are unveiled seemingly daily. In this dissertation, I first review the best practices and recent developments in molecular dynamics based alchemical free energy calculations in the AMBER molecular dynamics suite. I then present a graphics processor enabled implementation of alchemical free energy calculations with performance 360 times that of the existing CPU implementation, while maintaining equivalent accuracy through the judicious use of a combination of floating point and fixed precision. Next, I discuss the application of constant pH molecular dynamics to investigate the role of water in beta secretase-1 catalysis. This protein has a known pH dependence and is a key target in the fight against Alzheimer’s Disease. I present a hypothesis for the role of the flap region in regulating beta secretase-1 catalysis. Finally, I have investigated benzene egress from the binding pocket of the L99A mutant of T4 lysozyme using accelerated molecular dynamics. It is found that benzene exits the binding pocket by a multistep process from the buried cavity to ultimate release through an opening between the F/G, H and I helices.

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