Michael Shirts of the University of Virginia is supported by an award from the Chemical Theory, Models and Computational Methods program to develop methods to efficiently predict the thermodynamic properties of large numbers of chemical species and alternative models to describe these species using advanced statistical and simulation techniques. Predicting thermodynamic properties for a given chemical system via physical modeling is fundamentally a statistical estimation problem, but many potentially useful statistical techniques are not currently used in molecular simulation. This project applies several existing statistical techniques to the problem of thermodynamic property estimation for the first time and explores several novel simulation techniques. Most significantly, the project expands the ability of existing techniques for sampling from and computing thermodynamic properties of a few states to the exponentially large multidimensional spaces required for large-scale chemical property prediction and design.
Improved capabilities to optimize thermodynamic properties over chemical space would have impact in drug and materials design. Such capabilities would make exploring the properties of new proteins, structured heteropolymers, and other chemically complex heterogeneous systems much easier, potentially revealing new structural and functional frameworks that could not otherwise be discovered. For example, the proposed techniques would make it possible to optimize small molecules to have the tightest possible binding affinity across all single-point mutations of a given viral protein. It would also allow researchers to rapidly identify which proposed molecular models best describe natural chemical systems. The methods in this proposal will be implemented in GROMACS, a widely-used open source package of molecular dynamics software tools, making them accessible to large numbers of researchers. The findings and tools will be incorporated into Alchemistry.org, a web portal for sharing techniques, examples, and methods for free energy computations in classical molecular systems.
