Theoretical Studies of the Cytosol

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Toshiko Ichiye of Georgetown University is supported by an award from the Chemical Theory, Models and Computational Methods program in the CHE division to develop a new force field for simulations of biological macromolecules in the aqueous component of the cytosol. The Biophysics program in MCB is cofunding this proposal. New parameters are being developed for water, ions, and co-solutes found in the cytosol that are compatible for use with existing force fields for biological macromolecules. The force field is based on the soft sticky dipole-quadrupole-octupole (SSDQO) water model, which reproduces properties of liquid water over a range of temperatures and pressures and yet is computationally efficient. Initial solute targets are the ions Na+, K+, and Cl- and the co-solutes trimethylamine-N-oxide and urea, followed by other ions as well as osmolytes and metabolites typically found in the cell. The parameter optimization is being guided by quantum mechanical calculations and validated against experimental diffraction, thermodynamic, dielectric, and dynamic data. Developments in computer hardware are making possible simulations of biological macromolecules such as proteins and nucleic acids in cellular environments, which opens new horizons for understanding how they function in both normal and diseased states in real living systems. However, while much work has focused on developing the simulations of the biomolecules themselves, little attention has been paid on how to simulate the environment despite its importance for the structure and function of these molecules. Thus, a robust new force field for the components found in the cytosol is being developed to be compatible with existing force fields for the biomolecules. The force field is being implemented into CHARMM, a widely-used computer program for biological simulations, thus making it widely available to the scientific community. In addition, it is being implemented into lesson plans for the CHARMMing web-interface for CHARMM, thus promoting the education of new scientists throughout the world.