Classical MD with Mobile Protons, with Applications to Membrane Proteins

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The goal of this project is to enable proton movement between appropriate chemical groups in classical molecular dynamics computer simulations - methodology which allows calculation of proteins structures. This proton movement is important in a multitude of biochemical processes, such as pH titration of proteins, enzyme catalysis, proton channels, proton pumps, transporters, and the synthesis of ATP, the 'energy currency' of cells. Proton movement involves breaking and formation of covalent bonds, and classical simulations are normally not equipped to provide for this. This research will be carried out by undergraduate, graduate, and postdoctoral students at an institution with remarkable student diversity (53% of the students belong to underrepresented groups). The methods developed in this project will be made available to the research community through popular computer packages such as CHARMM.This project includes both method development and investigation of biological questions. The basis will be a recently developed hybrid Molecular Dynamics/Monte Carlo algorithm that allows proton movement between hydrogen-bonded partners at modest computational cost. This algorithm will be further developed, improved, and tested to ensure proper kinetics and thermodynamics in any environment and to extend its applicability to biological systems. It will draw from a number of state-of-the art methodologies for dealing with long time scales, adding its own contributions that are specific to proton transfer. It is expected to facilitate the better understanding of key biological processes that involve proton movement. The first biological systems to be studied include the M2 proton channel of the influenza virus and the Hv1 human proton channel.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.