The objective of this CAREER 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 use molecular dynamics (MD) simulation methods to develop insight into the factors that govern small-molecule associations in aqueous solutions, and to use this insight to guide the development of much faster but approximate simulation methods. First, unforced MD simulations will be used to study the association of pairs of rigid small molecules in explicitly-modeled aqueous solution. A variety of different molecule types will be studied in order to obtain unambiguous dissection of hydrophobic, electrostatic and hydrogen-bonding interactions. Molecule-types that combine these interactions will also be simulated to explore the way coupling of different interaction types affects associations. Second, similar MD simulations will be performed of rigid small-molecule associations in a wide range of salt solutions. Third, comparison of MD simulations in which small molecules are allowed internal degrees of freedom will reveal the extent to which conformational flexibility modulates associations. In all three aims attempts will be made to reproduce the explicit-solvent MD data with much faster but simpler Brownian dynamics (BD) methods. These comparisons will provide the necessary testing to enable thermodynamically-accurate BD simulations of large, subcellular systems to be performed.
The educational goals of this project will complement these aims and fill a considerable void in the academic course offerings of the University of Iowa by incorporating teaching of molecular simulation methods into the curriculum. In a first step, the teaching of MD methods will be integrated with an established Biophysical Chemistry course to provide a simulation perspective to experimental techniques. In a second, more ambitious step, an entirely new three semester hour course dedicated exclusively to molecular simulation methods will be developed. Teaching of this course will give access to new research methodologies, especially to students from the Biochemistry, Chemistry and Chemical Engineering Departments. The MD simulation data accrued during the course of this research will be made freely available to a broad scientific community developing novel molecular simulation methods.
