Dual Affiliation with Divisions of Engineering and Applied Science and With Chemistry and Chemical Engineering
The long-term objective of Professor Goddard's research has been to describe the properties of chemical, biological, and materials systems directly from first principles (without the necessity of empirical data). To accomplish this the group has been developing new theory, new methods, and new software. The group's approach builds from Quantum Mechanics (QM) through a hierarchy of more approximate methods suitable for longer length and times scales as indicated in the figure including Molecular Dynamics (MD), mesoscale dynamics, and macroscopic dynamics. The couplings between the length scales provide the means of determining the parameters [e.g. Force Fields (FF)] essential in the coarser descriptions.
BBE related applications focus on
G-Protein Coupled Receptors. The Goddard group has developed novel methods for predicting the three-dimensional structure by examining a complete set of 13 trillion possible rotations and tilting of the 7 transmembrane structures to select 25 thermally accessible packings.
Recent breakthroughs are finding that the G-Protein makes strong salt bridges to the 3 intracellular loops of the GPCR aligning the alpha-5 helix to be inserted into the GPCR upon activation. This allows the prediction of any of the many G-Proteins to any of the 800 GPCRs.
This has allowed the Goddard group to determine the mechanism by which the agonist activates the G-protein to release the GDP for exchange with GTP. It has also allowed them to determine which ligands activate beta-arrestin.
Current focus: Class A GPCRs: opioid, dopamine, GPR139: pain relief without addiction.
Class C: GABA agonists: structure, coupling with G-Protein and beta-arrestin, activation by agonists.
Class B: GLP1R agonists. structure, coupling with G-Protein and beta-arrestin, activation by agonists.
Class F: smoothened: structure, coupling with G-Protein and beta-arrestin, activation by agonists.