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Biomedical relevance: Key result in 2011: Structure of ribosome-SecY-complex resolved by MDFF (TR&D3)
10 studies published by BTRC, e.g.Villa et al. PNAS (2009) 106:1063-1068.Seidelt et al. Science (2009) 326:1412-1415.Becker et al. Science (2009) 326:1369-1373.Frauenfeld et al. Nat. Struct. Mol. Biol. (2011) 18:614-621.Agirrezabala et al. PNAS (2012) In press.
DBP 1: Structural analysis of ribosome by MDFF
Hybrid tools to integrate multi-resolution structural data
Frequent lack of complete crystallographic information require structure prediction tool
Complex communication pathway (e.g. decoding) require efficient MD simulations to elucidate
Computational challenges:
Future studies include a) translational fidelity and b) nascent chain folding and localization.
Over 50% of antibiotics target
Many related diseases. e.g. Alzheimer’s disease due to dysfunctional ribosome (J. Neuroscience 2005, 25:9171-9175)
Localization failure of nascent chain lead to neurodegenerative diseases (Mol. Bio. of the Cell 2005, 16:279-291)
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DBP Collaborators
Joachim Frank (Columbia U.)
Roland Beckmann (U. Munich)
Taekjip Ha (UIUC)
Kurt Fredrick (Ohio State U.)
Ruben Gonzalez (Columbia U.)
Cryo-EM Cryo-EM Single-molecule FRET
Mutagenesis experiments
Single-molecule FRET
Structure (2008), PNAS (2009), Proteins (2011), EMBO J. (2011), PNAS (2012)
Science (2009) x2, Nature Struct. Mol. Bio (2011),1 submitted
J. Mol. Bio. (2010), 1 submitted
New collaborator New collaborator
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Chen et al. Submitted. Jan 2012.Collaboration with Taekjip Ha (UIUC)
Recent Progress 2: Ribosome assembly simulated by Go model
Chen et al. Submitted. Jan 2012.Collaboration with Taekjip Ha (UIUC)Collaboration with Taekjip Ha (UIUC)
Recent Progress 2: Ribosome assembly simulated by Go model
Simulations of five-way junction in ribosomal small subunit revealed pathways of binding of
ribosomal protein S4 that assists folding.
Recent Progress 3: Translational stalling by SecM
Gumbart et al. Submitted. Mar 2012.Collaboration with Roland Beckmann (U. Munich)
Simulations of MDFF-derived ribosome-SecM model revealed stalling mechanism that
up-regulates expression of SecA
Recent Progress 4: Structural characterization of mRNA-tRNA translocation intermediates. Agirrezabala et al. PNAS 2012. In press. Collaboration with Joachim Frank (Columbia U.)
Recent Progress 4: Structural characterization of mRNA-tRNA translocation intermediates. Agirrezabala et al. PNAS 2012. In press. PNAS 2012. In press. PNASCollaboration with Joachim Frank (Columbia U.)
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TR&D 1 - NAMD TR&D 2 - VMD TR&D 3 – Cell Biology Software
Go potential Network analysis MDFF
QM/MM Improved vol. data manipulation MUFOLD-MDFF
GPU-acceleration of implicit solvent & grid force
Interactive MDFF MDFF for flexible regions
Polarizable force field for RNAs Interactive MDFF
TR&D Connections and Challenges
Network analysis; QM/MM;
Polarizable force field for RNAs
Structure determination of eukaryotic ribosome: building wheatgerm ribosome model from yeast ribosome
QM/MM
Translational fidelity: elucidate signaling pathway and GTP hydrolysis mechanism
MDFF; MUFOLD-
MDFF; Interactive
MDFF
Black: Completed; Green: To be completed
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