Multi-drug resistant bacteria present an increasing problem in US hospitals. To design new antibiotics that are effective against these bacteria, it is important to understand drug-target interactions and the targets themselves. We will study a major antibiotic target: the ribosome. Many ribosome antibiotics interfere with the process of decoding by the ribosome (""""""""tRNA selection""""""""). The rate-limiting step of decoding is accommodation, where the tRNA moves from a partially bound state (A/T state) to its fully bound position (A/A state) inside the ribosome. Structural biology techniques have determined the structure of the ribosome before and after accommodation. Kinetics experiments have determined accommodation rates. It is difficult, however, to study the process of accommodation in atomic detail experimentally. Molecular dynamics simulations have been used to study protein folding. However, until recently, the size of the ribosome has made simulations of ribosome conformational changes computationally prohibitive. We will use large-scale molecular simulation to study key features of accommodation, including the effect of the elongation factor EF-Tu and the effect of antibiotics. We will also combine molecular dynamics diffusion calculations together with measured kinetic rates to estimate accommodation barrier heights that correspond to these measured rates.

Public Health Relevance

Supercomputers will be used to simulate a major antibiotic target (the ribosome) in atomic detail. Understanding how antibiotics work will help lay the foundation for developing new drugs to combat resistant bacteria, a critical problem in US hospitals. Results will be validated against single molecule fluorescence experiments and structural biology experiments.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM072686-10
Application #
8518366
Study Section
Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Preusch, Peter C
Project Start
2005-07-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
10
Fiscal Year
2013
Total Cost
$304,136
Indirect Cost
$96,096
Name
Los Alamos National Lab
Department
Type
DUNS #
175252894
City
Los Alamos
State
NM
Country
United States
Zip Code
87545
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Whitford, Paul C; Sanbonmatsu, Karissa Y; Onuchic, José N (2012) Biomolecular dynamics: order-disorder transitions and energy landscapes. Rep Prog Phys 75:076601
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Zhang, Zhiyong; Sanbonmatsu, Karissa Y; Voth, Gregory A (2011) Key intermolecular interactions in the E. coli 70S ribosome revealed by coarse-grained analysis. J Am Chem Soc 133:16828-38

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