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the macromolecular motions database:

the macromolecular motions database:. ©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs. a standardized system for analyzing and visualizing macromolecular motions in a database framework. werner g. krebs Gerstein Lab/Molecular Biophysics & Biochemistry

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the macromolecular motions database:

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  1. the macromolecular motions database: ©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs a standardized system for analyzing and visualizing macromolecular motions in a database framework werner g. krebs Gerstein Lab/Molecular Biophysics & Biochemistry Yale University

  2. Source: http://cougar.slvhs.slv.k12.ca.us/~pboomer/physicstextbook/ch9.html I. Motions and Civilization: James Watt & the two-stroke engine • James Watt’s (1736-1819) most important improvement to the reciprocating steam engine (1769 patent) was the use of the double-action principle. In this system, the steam is used first on one side of the piston, then on the other.

  3. GroEL Source: http://www.cchem.berkeley.edu/~shkgrp/people/boisvert/thesis/ch2.html

  4. GroEL motion: “GroEL as a two-stroke engine” Image Credits: http://www.protein.bio.msu.su/biokhimiya/contents/v63/full/63040444.htm

  5. GroEL ©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs

  6. Source: http://www.ysbl.york.ac.uk/~barton/picture/cam/cam002.html Image Credit: http://www.ks.uiuc.edu/Research/cell_motility/actin/ Molecular Mechanism of Hebb Learning? Hebb rule of neural network learning: If two interconnected neurons are frequently activated together, the strengthof the connection between them should beincreased.

  7. Interpolation Engine 1: Adiabatic Mapping with a patched X-PLOR • The molecule is deformed in a series of small steps. (For the server, we divided the distance between starting and ending positions into an equal number of steps) • Energy minimization is performed after each step to produce structures with comparable energies. • Problems arise for large deformations if the energy minimization methods cannot effectively remove the accumulated stresses ©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs

  8. movie in science Volkman, B., Lipson, D., Wemmer, D. and Kern, D. "Two-state allosteric behavior in a single-domain signaling protein" (2001) Science. Published in March 23 Science. ©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs

  9. 30S ribosome RNA motion • Recently modified morph server software to analyze nucleic acid motions. • Completed custom morph of 30S subunit of ribosome for V Ramakrishnan, J Ogle et al.

  10. queue_manager

  11. Protein Morpher in Action ©2001 Werner G. Krebs. All Rights Reserved http://bioinfo.mbb.yale.edu/~wkrebs

  12. ©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs

  13. Testimonials 0 • “Some months ago I had submitted the coordinates of our glycerol kinase structure which revealed substantial domain motion…Well, the manuscript is heading to Biochemistry and I'd like to include a web address pointing to themorphed GK movie on your server … for the reviewers to look at…. Many thanks!” -- Dr. Cory Edward Bystrom, Ph.D. (via email) Formerly, Institute of Molecular Biology University of Oregon Presently, Senior Research Scientist New Zealand Diary Research Institute

  14. Testimonials I • “I really like the motions database….” -- Prof. Helen M. Berman, Ph.D. (in person) Professor of Chemistry Adjunct Professor, Biological Chemistry President, American Crystallographic Association, (1989-90). Director, RCSB Protein Data Bank Rutgers University New Brunswick, N.J

  15. Testimonials II • “I thinkyour morphing server would be a fabulouswayto get a feeling for the difference between two structureswhen RMS isn't useful.By making a movie, someone could see the ways in which two structures are similar or different. Have you used it for this purpose? This is what we wanted to do by submitting two structures to it. We have docked two tRNA structures in two different ways and wanted to "animate" the difference between the two dockings. Thanks, Russ.” -- Russ B. Altman, MD, PhD (via email) Associate Professor of Medicine (and Computer Science, by courtesy) Director, Biomedical Informatics Training Program Associate Director, Stanford Medical Scientist Training Program Thrust Leader, Molecular Science at NPACI/SDSC President, International Society for Computational Biology Stanford Medical Informatics Stanford University Medical Center 251 Campus Drive, MSOB X-215 Stanford, Ca 94305-5479

  16. Testimonials III • “Werner, you are the master, it looks so cool!My colleagues flip out about this….Thanks again and I hope we can keep in touch, I have more stuff about moving proteins coming.” -- Prof. Dorothee Kern, Ph.D. (via email) Assistant Professor of Biochemistry Dept. of Biochemistry, MS 009 Brandeis University Waltham, MA 02454-9110, USA

  17. Press Testimonials • Mentioned in NetWatch column, s.v. “Protein Shake” in Science (1999) 284(7), p. 871. • It was also noted by the HMS Beagle Biological Web Magazine as a “Web Pick”. • It is mentioned in Philip E Bourne, Judith Murray-Rust, Jeremy H Lakey Current Opinion in Structural Biology 1999, 9:9-10.

  18. How we add value Database of Macromolecular Motions Motions in PDB Database as fraction of all motions (not to scale)

  19. macromolecular motions • What are they? • Proteins, Nucleic Acids (Hammerhead) • Sidechains (trivial), Loops (LDH), Domains (ADK), Subunits (Hb) • When a Ligand Binds: Open, Closed • Essential link between structure and function • catalysis,regulation, transport, formation of assemblies, and cellular locomotion • A complicated biological phenomena that can be studied in quantitative detail • changes in thousands of atomic coordinates

  20. information, size, then packing based classification

  21. Calmodulin

  22. Snapshot of welcome screen

  23. Snapshot of motion entry

  24. HIV Reverse Transcriptase

  25. information, size, then packing based classification

  26. Citrate Synthase

  27. How we add value Database of Macromolecular Motions Motions in PDB Database as fraction of all motions (not to scale)

  28. How we add value II Database of Macromolecular Motions

  29. mechanisms of motions by packing • Packing classification is dominated by • Hinge (45%) • Unclassifiable (20%) • Shear (14%) categories ©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs

  30. mechanisms of motions by size ©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs

  31. fragment motions better studied Fragment • fragment motions (93% known) are better studied than domain motions (72% known) • most likely explanation: experimentalists better able to study smaller motions ©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs Domain

  32. percent studied by technique Other CD TRX • X-ray 95% • NMR 7% • MD 3% • TR X-ray 2% • CD 2% • Other 1% MD NMR ©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs X-ray

  33. Experimental Methods and Simulations Users Sequence/Structure Alignment Modified Sieve-Fit Superposition Screw-Axis Orientation 3 min Homogenization Database Information Interpolation Visual Rendering Web Report ©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs

  34. alcohol dehydrogenase ©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs

  35. diphtheria toxin (DT) Impossible morph; example of domain swapping. Not a true motion. ©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs

  36. conclusions • Macromolecular Database useful tool for obtaining information on protein and nucleic acid motions • Integrated morph server actually a software suite that homogenizes, interpolates, visualizes, and analyzesprotein and nucleic acid motions and stores results in database • Morph server can handle loosely related protein structures, so useful as a tool for evolutionary morphs as well as protein motions • Macromolecular Motions Database amendable to statistical analysis and automatic data-mining techniques • Data integrated into Partslist Database (http:/www.partslist.org) • Remains a fertile area of research ©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs

  37. acknowledgements • Prof. Mark Gerstein • Dr. Vadim Alexandrov • Nat Echols • Dr. Yuval Kluger • Dr. Jiang Qian • Cyrus Wilson • Hiyuan Yu • Ronald Jansen & Jochen Junker • Rest of Gerstein Lab • Research committee: • Prof. Dieter Soll • Prof. Jennifer Doudna • Rest of MB&B Faculty • Viewers Like You

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