DBP1: Ribosome
The ribosome translates genetic information into proteins. Due to its fundamental role in maintaining the cell and conserved differences between bacterial and eukaryotic ribosomes, over 50% of efforts developing antibiotics target bacterial ribosomes. The ribosome works with various partners to protect the newly synthesized polypeptide while co-translationally distributing proteins to specific target regions of the cell, e.g. with SecY for membrane protein insertion. The mistargeting of proteins during protein synthesis is a factor in several human neurodegenerative diseases, such as Alzheimer's disease. Due to its direct biomedical relevance, ribosome is a key topic among NIH- funded scientists and, according to Web of Science, has resulted in over 30,000 publications in the past 10 years.
MDFF model of a ribosome-SecY-nascent chain complex in a nanodisc.
Facing growing bacterial resistance to existing ribosomal antibiotics, researchers have been seeking multiple ways to develop new antibiotics targeting the ribosome at different stages of translation, which requires structural data and dynamics information at the atomic level of the ribosome system in functional states. However, current experimental investigations still lack a detailed picture of ribosome function and, therefore, limit the potential of the ribosome as a drug target. High resolution crystallography structures of the ribosome systems are usually confined to non-physiological crystalline states which deviate from functional states; structural data representing physiological states of the ribosome systems are mainly provided by cryo-electron microscopy (cryo-EM), but the resulting images lack the atomic detail needed for structure-based drug design. Furthermore, spatial and temporal resolution of experimental techniques are still orders of magnitude away from resolving ribosome dynamics at atomic resolution. Computational methods, such as the molecular dynamics flexible fitting (MDFF) method, developed by the Center, can bridge the resolution gap by fitting X-ray structures into cryo-EM maps to determine atomic models of ribosome systems at various functional states. Molecular dynamics (MD) simulations, in turn, can simulate ribosome dynamics in atomic detail.
Working closely with leading experimental scientists, the Center has been applying MDFF and MD simulations to investigate structures and dynamics of the ribosome. One of the achievements of the Center is the first atomic model of a ribosome-SecY-nascent chain complex in a membrane environment in which the nascent chain is being inserted into the membrane. Going forward, the Center will reach beyond the Escherichia coli ribosome and work on structure determination of eukaryotic ribosomes. The Center will also extend the time-scale and size of ribosome simulations to investigate various stages of translation, such as ribosome assembly, which requires long time-scale simulations, and decoding by the ribosome, which requires accurate simulations of the entire ribosome-cofactors system.
Computational studies of the ribosome serve as a test-bed for TR&D in the Center. First, structural determination of ribosomal systems of higher level organisms requires the enhanced MDFF suite from TR&D3-MDFF. Second, large scale simulations of ribosomal systems demand TR&D1 to develop a more efficient simulation engine delivering accurate force field treatment. Moreover, investigations of chemical reactions catalyzed by the ribosome requires TR&D1 to include quantum effects for MD simulations of large biomolecular systems. Finally, huge trajectories produced by ribosome simulations drive TR&D2 to promote efficient algorithms for visualization and analysis.
