Aaron R. Dinner

Scholar: 2005

Awarded Institution
Assistant Professor
The University of Chicago
Department of Chemistry


Research Interests

Molecular mechanisms and theoretical modeling of biological processes

Our group strives to understand molecular mechanisms of cellular dynamics through the development and application of theoretical approaches. It is a particularly exciting time in this area because experiments are now beginning to bridge the gaps in time and length scales between single molecules and whole cells. Interpretation of the resulting data depends on models, which in turn serve as the basis for formulation of specific hypotheses that drive future experiments. Theoretical approaches are powerful because they allow one to vary an individual parameter in a complex system to probe its role directly.

Current research falls in two broad areas:

Signaling in the immune system: The ability of cells in the immune system to integrate complex spatiotemporal signals from their environment is central to their mission to detect and destroy pathogens. Our work to date in this area has focused on understanding the role in T cell activation of the immunological synapse, an accumulation of receptors that forms at the intercellular junction between a mature T cell and an antigen presenting cell. Using a coarse-grained (lattice) model, we showed that different cell surface patterns could orchestrate distinct biological outcomes with a single set of intracellular signaling molecules. Taken together with recent imaging experiments, these results suggest that the synapse acts as an adaptive controller that both boosts receptor triggering and attenuates strong signals. More recently, we have been developing improved stochastic master equation methods to investigate the molecular basis for the remarkable sensitivity of T cells to agonist peptides. A single peptide can elicit a cellular response! 

DNA repair: Enzymes that maintain the integrity of our genetic material represent another form of protection that is vital for our survival. We are studying uracil-DNA glycosylase (UDG), which excises bases normally specific to RNA (uracil) that arise in DNA at a rate of several hundred per cell per day in humans. Using hybrid quantum-mechanical / molecular-mechanical (QM/MM) methods, we found that catalysis derives primarily from phosphate groups in the DNA backbone, rather than from the enzyme. The importance of the substrate electrostatic interactions resolved the long-standing biological conundrum that UDG mutants that lack key residues exhibit significant activity. Our current research in this area is focused on understanding substrate identification. Toward this end, we are improving methods for sampling rare events in molecular systems. In the process, we are continuing our development of the Monte Carlo module in CHARMM, a widely used program for modeling biological macromolecules in atomic detail.