CAREER: Computing accurate free energies for solubility, solvation, and transfer

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David Mobley, of the University of California, Irvine is supported by an award from the Chemical Theory, Models and Computational Methods program in the Chemistry Division and the Division of Advanced Cyberinfrastructure to develop, improve and use computer techniques to predict the properties of new molecules before they are created. Currently, in many cases, new molecules of interest must be made and tested to determine their properties such as their solubility, their likely distribution into the environment, or their interactions with important biomolecules. But the process of making (synthesizing) new molecules can be slow and expensive, and with the right computer tools (such as those advanced in this project), their properties can be predicted computationally in advance of their synthesis. This can result in substantial savings of time and money, since only compounds with desirable properties can then be synthesized. This project focuses on developing and applying computer tools to predict these properties, with a particular emphasis on three specific areas: Predicting solubilities, automating calculations to predict binding interactions, and predicting partitioning into different environments (i.e. in understanding environmental distribution and effects). A long-term goal is to provide researchers with well-validated computational tools which they can use to help guide research efforts designing new molecules.The proposed work develops and applies promising first-principles computational methods to predict thermodynamic properties such as solubilities (e.g. for dissolving a solid in water) and solvation thermodynamics for molecules in solution. This work builds on Dr. Mobley's previous methodological innovations in the area. Major new developments include a framework for physical, force-field-based solubility predictions, which will be tested with multiple force fields, and a new automated approach for conducting relative free energy calculations. A substantial emphasis is placed on software and workflow development to ensure the techniques developed and applied are easily accessible to other researchers. Methods and improvements from this work will be disseminated through the collaborative alchemistry.org website, featuring tutorials and background, and through software tools the investigator will release via Simtk.org, alchemistry.org, and elsewhere.