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.
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.
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|Pavlova, Anna; Gumbart, James C (2015) Parametrization of macrolide antibiotics using the force field toolkit. J Comput Chem 36:2052-63|
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|Hazel, Anthony; Chipot, Christophe; Gumbart, James C (2014) Thermodynamics of Deca-alanine Folding in Water. J Chem Theory Comput 10:2836-2844|
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|Gumbart, James C; Roux, BenoÃ®t; Chipot, Christophe (2013) Efficient determination of protein-protein standard binding free energies from first principles. J Chem Theory Comput 9:|
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