The objective of the proposed fellowship research is to elucidate the complex formation of the eubacterial proteins HU and IMF to unusual forms of DNA using the theory and methodologies of computational biophysics. Specific systems to be considered involve the proteins binding to highly bent forms of the DNA double helix that play a role in transcriptional regulation, site specific recombination and the initiation of replication, and to the four-way Holliday junction formed when DNA undergoes genetic recombination. The specific methods to be used are computationally intensive molecular dynamics and Monte Carlo simulations which require supercomputer facilities. The proteins, DNA, solvent water, and experimental salt conditions will be treated with a discrete all-atom model in the calculation of energies and forces. HU- and IHF-DNA complex formation at a high level of computational rigor and, in the process, enables the analysis of the free energy of binding in terms of the chemical forces acting at critical junctures. The new knowledge obtained in this research will provide a basis for the interpretation of experimental results and an understanding of the mechanisms of action in these biological processes at the sub-molecular level.

Public Health Relevance

Special proteins activate DNA and facilitate gene expression. The goal of this proposal is to use modern computational techniques to learn how these proteins interact with DNA. Understanding the control over these interactions is critical in the development of agents used to fight disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32GM087101-01
Application #
7615976
Study Section
Special Emphasis Panel (ZRG1-F04B-P (20))
Program Officer
Flicker, Paula F
Project Start
2009-01-15
Project End
2012-01-14
Budget Start
2009-01-15
Budget End
2010-01-14
Support Year
1
Fiscal Year
2009
Total Cost
$47,210
Indirect Cost
Name
Wesleyan University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
145683954
City
Middletown
State
CT
Country
United States
Zip Code
06459
Wheatley, Elizabeth G; Pieniazek, Susan N; Mukerji, Ishita et al. (2012) Molecular dynamics of a DNA Holliday junction: the inverted repeat sequence d(CCGGTACCGG)ýýý. Biophys J 102:552-60
Kormos, Bethany L; Pieniazek, Susan N; Beveridge, David L et al. (2011) U1A protein-stem loop 2 RNA recognition: prediction of structural differences from protein mutations. Biopolymers 95:591-606
Pieniazek, Susan N; Hingorani, Manju M; Beveridge, D L (2011) Dynamical allosterism in the mechanism of action of DNA mismatch repair protein MutS. Biophys J 101:1730-9