Abstract:
The functions of biomolecules are governed largely by their dynamics. Elucidation of changes in molecular conformation, as well as interactions between molecules is thus vital for a deep understanding of broader biological processes, such as the binding of drugs to their molecular receptors. Molecular dynamics (MD) simulation is a powerful complement to experimental studies in that these dynamics can be observed at atomic resolution, providing a bridge between structure and function. However, the impact of MD is limited by three challenges: sampling, complexity, and scope. Here, I will describe some of my recent work and how it addresses these challenges using ideas from network theory. I will describe WExplore, a novel enhanced sampling algorithm that explores transient or "cryptic" states, which can be separated from the crystallographic structure by large free energy barriers. Also, by creating and manipulating configuration space networks, I examine the largest protein folding trajectory dataset in toto and reveal fundamental properties of how proteins fold. I then show how the same analysis toolkit can be applied to systems-level data, by examining the cooperation and competition between chaperone subsystems in E. coli using the FoldEco program. Together, this set of generally applicable tools will help provide the foundation for future MD studies, and help to address the challenges of sampling, complexity and scope.

Biography:
Alex Dickson received his Ph.D. from the University of Chicago under Professor Aaron Dinner. There he developed new computational approaches to enhance the sampling of simulations that are driven out of equilibrium. Applications spanned from biomolecular systems, such as an RNA unfolding in a flowing solvent, to model systems from physics, such as sheared Ising models. In 2011, he began as a postdoctoral researcher with Professor Charles L. Brooks III at the University of Michigan in Ann Arbor, where he continued developing new enhanced sampling methods for application to atomistic biomolecular systems. A novel method, "WExplore," allows for enhancement of sampling in an undirected fashion, and has been used to observe a wide variety of rare biomolecular phenomena. He also developed a set of analysis techniques that can help visualize the entire space of possible biomolecular conformations in a network plot.

Dickson's group will employ a wide range of computational tools to address fundamental questions in molecular biology and medicinal chemistry. Using approaches that explicitly simulate the motions of drug receptors, his group will: find small molecules (drugs) that are designed to block flexible protein-protein interaction sites, and examine binding of drugs currently in the design process to improve their kinetic properties.

Host:
Dr. Metin Aktulga