The advent of higher resolution cryo electron microscopy and structures of eukaryotic ribosomes has opened the field of ribosome mechanism to a vast array of possibilities. Together with the Christian Spahn cryo-EM lab, we recently published one of the first all-atom models of the human ribosome in various functional states related to decoding. Using our MDfit method, we produced models highly consistent with cryo-EM density. The study revealed a new conformational change specific to eukaryotes: subunit rolling. We have also performed extensive studies on tRNA accommodation into the bacterial ribosome. Here, we will investigate the effect of subunit rolling on accommodation during decoding by the mammalian ribosome. We will also study conformational changes occurring prior to decoding and after accommodation. By comparing human and bacterial ribosome mechanism, we hope to gain insight into antibiotic action mechanism. We will use a combination of explicit solvent and all-atom reduced description techniques based on our previous publications. We will also extend our MDfit technique for higher resolution cryo-EM density.
The advent of higher resolution cryo electron microscopy and structures of eukaryotic ribosomes has opened the field of ribosome mechanism to a vast array of possibilities. We will expand on our published studies of tRNA accommodation and human ribosomal decoding, producing simulations of the decoding process in humans. By comparing human and bacteria ribosome mechanism, we hope to gain new insight into antibiotic mechanism.
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|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|
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|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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