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Appointments:
Assistant Professor
Department of Chemistry
Committee on Immunology
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Education:
Ph.D., Harvard University, 1999
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Contact:
Phone: (773) 702-2330
Fax:
(773) 834-5250
E-Mail:
dinner@uchicago.edu
Lab:
dinner-group.uchicago.edu
Address:
The University of Chicago
GCIS E139E
929 East 57th Street
Chicago, Illinois 60637
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Related Research Interests:
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Aaron Dinner, Ph.D.
Molecular Mechanisms of Cellular Dynamics through the
Development and Application of Theoretical Approaches
Research Summary
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 improving gene therapy and 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.
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 novel means for
studying dynamics in complex systems and applied them to a DNA repair
system.
Gene regulation
during development of the immune system
Computational approaches are important for understanding how cell-fate
decisions are made because the cooperative nature of the dynamics
hinders intuition of responses to experimental probes. We are thus
integrating experimental data to construct phenomenological models for
the gene regulatory networks that control lineage specification of
myeloid and lymphoid cells. Presently, we are exploring various
approaches beyond the mean-field to better be able to link antigen
receptor specificity with development.
Automated reaction
network discovery
Due to the availability of high throughput experimental methods for
measuring molecular populations, interpretation of data is now often
the bottleneck in assembling gene regulatory and signaling networks.
Computational methods can address this problem by identifying molecular
circuits consistent with measurements. These networks can in turn be
used to design further experiments to discriminate between the
suggested mechanisms. The methods that we use to integrate the rate
laws that govern gene expression are quite similar in form to those
that we use to propagate the positions of atoms in our
atomic-resolution studies of DNA-binding proteins. We are seeking to
exploit this fact, together with advances in simulation methods for
treating complex systems, to improve procedures for fitting
experimental data.
Spatial control of
reactions within cells
The gene regulatory and signaling network studies above provide
examples of all-or-none responses to smooth variations in levels of
molecular species. The fact that quantitative differences in protein
levels can give rise to qualitative changes in cellular behavior allows
developmental programs to be controlled simply through spatial
localization of proteins. Because localization is often mediated by the
cytoskeleton, we are developing computational algorithms for treating
nucleation, growth, and reorganization of actin filament networks.
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Selected Papers
Ma A, and Dinner AR. (2005). An automatic method for identifying
reaction
coordinates in complex systems. J. Phys. Chem. 109, 6769-6779.
Warmflash A, and Dinner AR. (2005). A model for TCR gene use. J.
Immunol., 177, 3857-3864.
Laslo P, Spooner CJ, Warmflash A, Lancki DW, Lee H-J, Sciammas R,
Gantner BN, Dinner AR, and Singh H. (2006). Multilineage
transcriptional
priming and stabilization of alternate hematopoietic cell fates. Cell,
126, 755-756.
Hu J, Ma A, and Dinner AR. (2006). Monte Carlo simulations of
biomolecules: The MC module in CHARMM. J. Comp. Chem. 27, 203-216.
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Faculty and Research
Programs
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