Infectious diseases are the second leading cause of death in the world. With novel classes of antibiotic drugs virtually nonexistent, and the resistance of pathogenic bacteria to current ones increasing rapidly, the development of new approaches is becoming an imperative for advancing human health efforts. Molecular modeling will play an essential role in these new approaches, due to the fundamentally atomic-scale nature of the critical structures, processes, and interactions underlying the action of both antibacterial agents and resistance mechanisms. In order to illuminate these structures and processes, the PI will focus on three systems specific and essential to bacteria: the bacterial cel wall, the outer membrane, and the SecA protein translocase. The cell wall provides shape and strength to bacteria, and is a canonical antibacterial target, yet its mesoscale structure remains unknown. In the first aim, the interaction of the enzymes synthesizing the cell wall with its underlying components will be modeled, permitting novel antibacterial agents that can also overcome drug resistance to be developed. In Gram-negative bacteria, the outer membrane rests beyond the cell wall and presents one of the greatest barriers to the entry of drug molecules. Furthermore, by modulating the few available entry pathways through existing protein channels, it plays a crucial role in drug efficacy. In the second aim, the PI will quantify this modulation and its effect on drug influx. Finally, in the third aim, the PI will determine the functional cycle of SecA, an ATP driven motor that enables the translocation of nascent proteins across membranes. By using structural data generated in the process, SecA will be exploited as a novel antibacterial target.
All aims rely on advanced computational tools and methods, including cutting-edge molecular dynamics simulations. These simulations, which furnish dynamic views spanning a wide range of length and time scales, are enabled, in particular, by the emergence of petascale supercomputing resources and the software necessary to take full advantage of them.

Public Health Relevance

The threat posed by bacterial infection is growing rapidly, despite efforts over nearly a century to keep it in check. This projects aims to limit its advance by revealing bacterial-specific structures and processes at an unprecedented level of detail, thus enabling the next generation of rational drug design.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Career Transition Award (K22)
Project #
1K22AI100927-01
Application #
8351847
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Korpela, Jukka K
Project Start
2013-05-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$161,090
Indirect Cost
$11,090
Name
Georgia Institute of Technology
Department
Physics
Type
Schools of Arts and Sciences
DUNS #
097394084
City
Atlanta
State
GA
Country
United States
Zip Code
30332
Nguyen, Lam T; Gumbart, James C; Beeby, Morgan et al. (2015) Coarse-grained simulations of bacterial cell wall growth reveal that local coordination alone can be sufficient to maintain rod shape. Proc Natl Acad Sci U S A 112:E3689-98
Comer, Jeffrey; Gumbart, James C; Hénin, Jérôme et al. (2015) The adaptive biasing force method: everything you always wanted to know but were afraid to ask. J Phys Chem B 119:1129-51
Pavlova, Anna; Gumbart, James C (2015) Parametrization of macrolide antibiotics using the force field toolkit. J Comput Chem 36:2052-63
Chen, Yu; Bauer, Benedikt W; Rapoport, Tom A et al. (2015) Conformational Changes of the Clamp of the Protein Translocation ATPase SecA. J Mol Biol 427:2348-59
Johnson, Jennifer L; Entzminger, Kevin C; Hyun, Jeongmin et al. (2015) Structural and biophysical characterization of an epitope-specific engineered Fab fragment and complexation with membrane proteins: implications for co-crystallization. Acta Crystallogr D Biol Crystallogr 71:896-906
Noinaj, Nicholas; Kuszak, Adam J; Balusek, Curtis et al. (2014) Lateral opening and exit pore formation are required for BamA function. Structure 22:1055-62
Hazel, Anthony; Chipot, Christophe; Gumbart, James C (2014) Thermodynamics of Deca-alanine Folding in Water. J Chem Theory Comput 10:2836-2844
Gumbart, James C; Beeby, Morgan; Jensen, Grant J et al. (2014) Escherichia coli peptidoglycan structure and mechanics as predicted by atomic-scale simulations. PLoS Comput Biol 10:e1003475
Jiang, Wei; Phillips, James C; Huang, Lei et al. (2014) Generalized Scalable Multiple Copy Algorithms for Molecular Dynamics Simulations in NAMD. Comput Phys Commun 185:908-916
Gumbart, James C; Roux, Benoît; Chipot, Christophe (2013) Efficient determination of protein-protein standard binding free energies from first principles. J Chem Theory Comput 9:

Showing the most recent 10 out of 15 publications