Knowledge about the three dimensional structure of ribonucleic acids (RNAs) and ribonucleoprotein particles (RNPs) is essential for understanding how they carry out their biological functions, which include RNA processing and the translation of the genetic information of mRNA into protein sequences. Such understanding could offer opportunities for pharmacological or genetic intervention in these critical processes. This proposal describes the development of three dimensional models for RNAs and RNPs, with emphasis on the ribosome and ribonuclease P (RNase P). We will produce both low resolution models and all-atom models, using automated and manual methods for integrating information from a wide range of experiments. The level of detail in each model depends on the available data and the importance of the region under consideration. The low resolution models identify the location of individual nucleotides and proteins. They are generated by an automated structure refinement protocol using our molecular modeling package, YAMMP. All-atom models are built using the MC-SYM program, written by Dr. Francois Major (University of Montreal), and refined with YAMMP. The protocols produce a collection of models that are compatible with the experimental data, and a consensus model can be derived from this collection. The methods provide an estimate of the statistical uncertainty (resolution) of the consensus model, and they identify conflicts in the experimental data. This proposal discusses the investigation of specific problems related to the structure of the ribosome and RNase P, in collaboration with three experimentalists. It also describes extensions and improvements to the methods for both low resolution and all-atom modeling, along with the development of mixed mode models with all-atom representation in some regions and low resolution representation in others.
| Taylor, Derek J; Devkota, Batsal; Huang, Andrew D et al. (2009) Comprehensive molecular structure of the eukaryotic ribosome. Structure 17:1591-1604 |
| Mears, Jason A; Sharma, Manjuli R; Gutell, Robin R et al. (2006) A structural model for the large subunit of the mammalian mitochondrial ribosome. J Mol Biol 358:193-212 |
| Stagg, Scott M; Harvey, Stephen C (2005) Exploring the flexibility of ribosome recycling factor using molecular dynamics. Biophys J 89:2659-66 |
| Stagg, Scott M; Mears, Jason A; Harvey, Stephen C (2003) A structural model for the assembly of the 30S subunit of the ribosome. J Mol Biol 328:49-61 |
| Gao, Haixiao; Sengupta, Jayati; Valle, Mikel et al. (2003) Study of the structural dynamics of the E coli 70S ribosome using real-space refinement. Cell 113:789-801 |
| Mears, Jason A; Cannone, Jamie J; Stagg, Scott M et al. (2002) Modeling a minimal ribosome based on comparative sequence analysis. J Mol Biol 321:215-34 |
| Stagg, Scott M; Valle, Mikel; Agrawal, Rajendra K et al. (2002) Problems with the transorientation hypothesis. RNA 8:1093-4 |
| Stagg, S M; Frazer-Abel, A A; Hagerman, P J et al. (2001) Structural studies of the tRNA domain of tmRNA. J Mol Biol 309:727-35 |
| VanLoock, M S; Agrawal, R K; Gabashvili, I S et al. (2000) Movement of the decoding region of the 16 S ribosomal RNA accompanies tRNA translocation. J Mol Biol 304:507-15 |
| Wang, R; Alexander, R W; VanLoock, M et al. (1999) Three-dimensional placement of the conserved 530 loop of 16 S rRNA and of its neighboring components in the 30 S subunit. J Mol Biol 286:521-40 |
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