VIRTUAL
 
Thursday, January 28th , 2021
3:45 – 4:45 p.m.
WEBEX
 
  
Speaker:  Karissa Sanbonmatsu
 
T-6: THEORETICAL BIOLOGY AND BIOPHYSICS
LANL
 
 
“The Resolution Revolution: Merging Cryogenic Electron Microscopy (cryo-EM) with HPC Molecular Simulations in Structural Biology
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Abstract: 
The advent of the direct detector camera and other related technologies has produced rapid growth in the field of cryogenic electron microscopy (cryo-EM). The so-called ‘resolution revolution’ has made cryo-EM the tool of choice in structural biology, where large biomolecular complexes are imaged at near-atomic resolution.  Interestingly, cryo-EM has played a key role in understanding the SARS-CoV-2 virus, which is the causative agent of the COVID-19 pandemic. The explosion of new data from high-resolution cryo-electron microscopy (cryo-EM) studies has produced a large number of datasets for many biomolecular complexes in various functional states, creating a high demand for atomistic models corresponding to these high resolution data. Here, we present an automated fitting technique for high-resolution cryo-EM data sets that produces all-atom models highly consistent with the EM density (Ratje, et al., Nature 2010; Budkevich, et al., Cell 2014). Using a molecular dynamics approach, atomic positions are optimized with a potential that includes the cross-correlation coefficient between the structural model and the cryo-EM electron density, as well as a biasing potential preserving the stereochemistry and secondary structure of the biomolecule (Kirmizialtin et al., Methods in Enzymology, 2015; Kim, et al., J. Structural Biology 2019). We focus on the ribosome, a major target for biothreat-related antibiotics. Obtaining atomistic models of the ribosome consistent with high-resolution cryo-EM reconstructions at many functional states, we perform molecular dynamics simulations, merging cryo-EM and single molecule FRET experiments (Whitford, et al., J. Am. Chem. Soc. 2010; Morse, et al., PNAS 2020; Girodat, et al., J. Mol. Biol. 2020). By investigating the kinetics and thermodynamics of tRNA movement through the ribosome, we produce new insight into the operational principles this molecular machine, which plays a fundamental role in all life forms.