The objective of this project, jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences and the Theoretical and Computational Chemistry Program in the Chemistry Division, is to develop a polarizable CHARMM force field, based on the charge equilibration formalism, applicable to classical statistical mechanical computations with a particular focus on membranes and integral membrane proteins and to apply it to study ion translocation properties in a simple, model ion channel, Gramicidin A, for which there has been long-standing indication of the need for explicit treatment of electronic polarization to quantitatively describe channel conductance derived from potentials of mean force computed from detailed, all-atom molecular dynamics simulations. The project will build on ongoing preliminary work toward a first-generation polarizable force field for proteins; focusing predominately on deriving relevant parameters for lipids and membrane bilayer components, and a series of monovalent ions. This will involve application of a combination of quantum mechanical and classical simulations (MD of pure bulk liquids) to determine the electrostatic and non-bonded parameters defining the CHARMM-FQ potential. Following modification of force constants of intramolecular potentials, the force field will be validated via application to simulations of lipid bilayers as membrane models. Finally, umbrella-sampling methods will be employed to compute a potential of mean force for a series of monovalent ions translocating through the Gramicidin A channel.
There is significant potential for broad impact on the general scientific community of biophysicists, and more specifically on those modeling membrane systems such as ion channels and transporters. The rigorous development and application of polarizable force fields for to large biomacromolecular systems is a necessary step in advancing understanding of these systems. Furthermore, for ion channels there is a vast amount of information to be gleaned from simulations using polarizable force fields, since the physics of such systems is critically dependent on a precise balance between interactions that will be provided by polarizable interaction potentials. This research also provides educational and training opportunities for postdoctoral scholars and graduate students. Due to the broad spectrum of methodologies (ranging from ab initio/DFT methods to continuum based macroscopic methods such as Brownian Dynamics and electro-diffusion theory) required to address the various aspects of force field development and application to ion channels, there is tremendous scope for learning; equally important, the integration of techniques will allow a broad understanding of the interconnections of available technologies in solving scientifically oriented problems, in this case within the realm of biophysics. Finally, all of the code development and force field parameters associated with the CHARMMFQ force field will be available to academic laboratories via distribution of the CHARMM academic license and from our web site (for the force field parameters).