Understanding details of how living cells signal and coordinate complex cellular activities is an unsolved problem of high fundamental significance. It is known that cells are comprised of an array of molecules, and therefore the interactions among these molecules at a specific time and location are potentially responsible for functional outcomes. It remains challenging to quantify intermolecular interactions between a pair of molecules at atomic scale, owing largely to a poor understanding of underlying dynamic motions. Importantly, many such structural motions in biomolecules such as proteins cannot be directly inferred from high-resolution static experimental structures, and therefore novel methods to probe dynamic motions are needed. In this project, the unique combination of atomically-resolved molecular simulations with various experimental techniques establishes new approaches to study protein-protein interactions, and the small molecules developed may lead to tools for controlling such interactions. The graduate and postdoctoral researchers working on this project acquire interdisciplinary training in computer simulation approaches for proteins and experimental approaches involving protein characterization and spectroscopic methods, thereby gaining an appreciation for ways in which theory and experiment can inform each other. The outreach activities of this project educate and train high school students and teachers in STEM disciplines via hands-on lab experiences. The resulting tools such as software, structural models, and protein constructs are demonstrated in chemical engineering, biophysics, and pharmacology courses, and are disseminated among the broader scientific community via workshops, symposia, and meetings.
This research project employs large-scale molecular simulation techniques on all-atom models of proteins to infer underlying dynamics, discover hidden conformational states, and quantify interactions at protein-protein interfaces. A variety of computational approaches are pursued including classical molecular dynamics simulations in explicit solvent, methods for enhanced conformational sampling and thermodynamic characterization of proteins, and Monte Carlo protocols for small molecule docking. To gain a better understanding of dynamics and interactions, the modeling and simulation effort are integrated with many experimental (biochemical, biophysical, and spectroscopic) techniques at various levels. These combined tools are used to study regulators of G-protein signaling (RGS) proteins using thiadiazolidinone (TDZD) analogues as small molecule chemical probes. The focus is to quantify differences in dynamics of three-different RGS proteins that result in differences in specificity and potency for different small molecules, and discover the mechanisms by which small molecules affect and inhibit interactions between various RGS proteins and activated G-alpha subunits of G-proteins. The quantification of mechanisms and interactions in this family of proteins may reveal the extent to which dynamic motions play a role in regulating protein-protein interactions, and the unique ways in which such motions can be exploited for targeting protein-protein interfaces.
