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

  • Author(s): Mermelstein, Daniel Janson
  • Advisor(s): McCammon, James A
  • Walker, Ross C
  • et al.
Abstract

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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