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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function D Study Section (MSFD)
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Preusch, Peter C
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Los Alamos National Lab
Los Alamos
United States
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Liu, Wei; Shin, Dongwon; Ng, Martin et al. (2017) Stringent Nucleotide Recognition by the Ribosome at the Middle Codon Position. Molecules 22:
Budkevich, Tatyana V; Giesebrecht, Jan; Behrmann, Elmar et al. (2014) Regulation of the mammalian elongation cycle by subunit rolling: a eukaryotic-specific ribosome rearrangement. Cell 158:121-31
Kaushal, Prem S; Sharma, Manjuli R; Booth, Timothy M et al. (2014) Cryo-EM structure of the small subunit of the mammalian mitochondrial ribosome. Proc Natl Acad Sci U S A 111:7284-9
Whitford, Paul C; Sanbonmatsu, Karissa Y (2013) Simulating movement of tRNA through the ribosome during hybrid-state formation. J Chem Phys 139:121919
Whitford, Paul C; Blanchard, Scott C; Cate, Jamie H D et al. (2013) Connecting the kinetics and energy landscape of tRNA translocation on the ribosome. PLoS Comput Biol 9:e1003003
Hayes, Ryan L; Noel, Jeffrey K; Mohanty, Udayan et al. (2012) Magnesium fluctuations modulate RNA dynamics in the SAM-I riboswitch. J Am Chem Soc 134:12043-53
Shi, Xinying; Khade, Prashant K; Sanbonmatsu, Karissa Y et al. (2012) Functional role of the sarcin-ricin loop of the 23S rRNA in the elongation cycle of protein synthesis. J Mol Biol 419:125-38
Ahmed, Aqeel; Whitford, Paul C; Sanbonmatsu, Karissa Y et al. (2012) Consensus among flexible fitting approaches improves the interpretation of cryo-EM data. J Struct Biol 177:561-70
Whitford, Paul C; Sanbonmatsu, Karissa Y; Onuchic, José N (2012) Biomolecular dynamics: order-disorder transitions and energy landscapes. Rep Prog Phys 75:076601
Sanbonmatsu, Karissa Y (2012) Computational studies of molecular machines: the ribosome. Curr Opin Struct Biol 22:168-74

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