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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