 |
| Born Chicago, Illinois, 1972. |
| Harvard University, A.B., 1994, Ph.D., 1999 |
| University of Oxford, 1999-2001. |
| University of California, Berkeley, 2001-2003. |
| University of Chicago, Assistant Professor, 2003- |
| |
| Accolades |
| 2008 Alfred P. Sloan Fellow. |
| 2006 NSF CAREER Award. |
| 2005 Searle Scholar. |
| 2003 Dreyfus New Faculty Award. |
| 2000-2001 Linacre College EPA Cephalosporin Junior Research Fellow. |
| 1999 Burroughs Wellcome Fund Hitchings-Elion Postdoctoral Fellow. |
| 1994-1999 Howard Hughes Medical Institute Predoctoral Fellow. |
|
|
| Aaron Dinner |
| Assistant Professor |
|
|
| |
| Research Interests |
The
Dinner group develops and applies theoretical methods for relating
cellular behavior to molecular properties. We are particularly
interested in how proteins regulate access to genes in the context of
the development of the immune system. Understanding how such complex
behavior arises from physical and chemical features is a problem in
fundamental statistical mechanics, but its solution has direct
implications for treating autoimmune pathologies and cancers as well as improving
vaccination strategies.
One feature that makes
theoretical studies of cellular behavior challenging is that the
relevant dynamics span a hierarchy of time and length scales ranging
from Angstroms and femtoseconds to micrometers and minutes. Experiments
are now beginning to bridge gaps in spatial and temporal resolution,
and models are vital for design and interpretation of such
measurements. Our research thus blends atomic-resolution simulations
with coarse-grained numerical and analytical approaches, often in
collaboration with experimental groups. |
| |
| Gene regulation during development and function of the immune system |
| Over
the last decade, advances in techniques for characterizing
molecular populations and positions in cells have driven a revolution in
our systems-level understanding of biological design principles. In
particular, a dialog between theory and experiment has revealed how cells
process information about their environments to make decisions despite inherent
noise. However, the bulk of this work has
been in relatively simple unicellular organisms. There is now the opportunity to begin making similar progress in cells of
higher organisms, which can reveal new emergent behaviors.
We are thus integrating experimental data to construct phenomenological models
for the gene regulatory networks that control myeloid and lymphoid cell fate
choice in mammalian blood. These studies are important from a biological perspective because the
cooperative nature of the dynamics hinders intuition of responses to
experimental probes. Motivated by these studies, we have also explored
systematic analytical treatments of master equation representations of
cell signaling and gene expression. These models account for stochastic effects and the discrete nature of copy
numbers of participating molecules. |
| |
| Path sampling reveals the dynamics of DNA binding at atomic-resolution |
DNA
transcription, recombination, replication, and repair are all regulated
by proteins that bind specific sites on DNA. Despite small copy numbers
in cells, such proteins can locate target elements among billions of
base pairs thousands of times faster than allowed by a
three-dimensional random walk. To objectively evaluate how putative
search mechanisms arise in specific molecular situations, which is
essential to ultimately be able to make defined interventions,
atomic-resolution simulations based on transferable potentials are
required.
Building on the transition path sampling framework introduced
by David Chandler and co-workers, we have introduced general means for
harvesting and statistically characterizing rare events in complex systems and applied them to understand how a DNA repair
protein searches for damage. |
| |
| Nonequilibrium statistical mechanics |
| Because
biological systems operate far from equilibrium, our research on specific
problems often touches on general issues at the forefront of fundamental
statistical mechanics. Here, my group and I are striving to develop systematic
means for projecting complex dynamics onto a small number of degrees of
freedom. Doing so is essential for connecting models with single-molecule measurements that
probe dynamics, including in cellular contexts. A major
contribution that we made in this area was the introduction of an
umbrella-sampling-like algorithm for determining the steady-state probability distribution of
an ergodic system arbitrarily far from equilibrium. We also proved
analytically that projection shifts the distribution of single-trajectory entropies on which
fluctuation theorems (FTs) are based towards one characteristic of an
equilibrium process. Such studies are important because FTs provide hints of a
unified theoretical framework for systems far from equilibrium. |
| |
| Selected References |
| 1. Li, Y., Qu, X., Ma, A., Smith, G. J., Scherer, N. F. & Dinner, A. R. Models of single-molecule experiments with periodic perturbations reveal hidden dynamics in RNA folding. J. Phys. Chem. B, 113, 7579-7590 (2009). |
| 2. Dickson, A., Warmflash, A., & Dinner, A. R. (2009) Nonequilibrium umbrella sampling in spaces of many order parameters. J. Chem. Phys., 130, 074104 (2009). |
| 3. Warmflash, A. & Dinner, A. R. (2008) Signatures of combinatorial regulation in intrinsic biological noise. Proc. Natl. Acad. Sci. USA, 17262-17267 (2008). |
| 4. Hu, J.; Ma, A.; Dinner, A. R. A two-step nucleotide-flipping mechanism enables kinetic discrimination of DNA lesions by AGT. Proc. Natl. Acad. Sci. USA, 105, 4615-4620 (2008). |
| 5. Li, Y.; Bhimalapuram, P.; Zhao, T.; Dinner, A. R. How the nature of an observation affects single-trajectory entropies. J. Chem. Phys., 128, 074102 (2008). |
| 6. Warmflash, A.; Bhimalapuram, P.; Dinner, A. R. Umbrella sampling for nonequilibrium processes. J. Chem. Phys., 127, 154112 (2007). |
| 7. Warmflash, A. & Dinner, A. R. A model for TCR gene segment use. J. Immunol. 177, 3857-3864 (2006). |
| 8. Laslo, P.; Spooner, C. J.; Warmflash, A.; Lancki, D.W.; Lee, H.-J.; Sciammas,
R.; Gantner, B.N.; Dinner, A.R.; Singh, H. Multilineage transcriptional
priming and stabilization of alternate hematopoietic cell fates. Cell, 126, 755-756 (2006). |
| 9. Hu, J., Ma, A. & Dinner, A. R. Monte Carlo simulations of biomolecules: The MC module in CHARMM. J. Comp. Chem. 27, 203-216 (2006). |
| 10. Ma, A.; Dinner, A. R. An automatic method for identifying reaction coordinates in complex systems. J. Phys. Chem. 109, 6769-6779 (2005). |
| |
|
Physical Chemistry 