molmovdb: database of molecular movements anastasia kurdia
TRANSCRIPT
![Page 1: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/1.jpg)
MolMovDB:Database of molecular
movements
Anastasia Kurdia
![Page 2: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/2.jpg)
Motivation
Motion is closely related to the way a structure fulfills a particular function, and protein motion is involved in wide variety of basic protein functions
Studying motions provides an insight into function
![Page 3: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/3.jpg)
Motivation
Rapidly increasing amount of data characterizing protein structure (X-ray crystallography, NMR, computational data)
Classification of motions helps in predicting protein function
![Page 4: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/4.jpg)
![Page 5: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/5.jpg)
Motivation
• Need for data storage and management
• Need for an efficient mechanism to relate the structures one to another, beyond classification based on sequence or structural alignment.
![Page 6: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/6.jpg)
MolMov database
• Storing motions• Obtaining motions• Classification of
motions• Standardized
statistics and quantitative measures
• Unified nomenclature for protein motions
Movies as database entries
Custom software tool to perform service tasks – morph server
![Page 7: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/7.jpg)
![Page 8: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/8.jpg)
Protein motions
Manually maintained descriptions of conformational changes in hundreds of distinct proteins, with references and movie links.
![Page 9: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/9.jpg)
Possible ways a motion can be classified
[D-s-2] Known Domain Motion, Shear Mechanism [D-h-2] Known Domain Motion, Hinge Mechanism [D-?-2] Known Domain Motion, Unclassifiable Mechanism [D-n-2] Known Domain Motion, Neither Hinge nor Shear Mechanism [D-f-2] Known Domain Motion, Partial Refolding of Structure [D-s-1] Suspected Domain Motion, Shear Mechanism [D-h-1] Suspected Domain Motion, Hinge Mechanism [D-?-1] Suspected Domain Motion, Unclassifiable Mechanism [D-n-1] Suspected Domain Motion, Neither Hinge nor Shear Mechanism [F-s-2] Known Fragment Motion, Shear Mechanism [F-h-2] Known Fragment Motion, Hinge Mechanism [F-?-2] Known Fragment Motion, Unclassifiable [F-n-2] Known Fragment Motion, Neither Hinge nor Shear Mechanism [F-s-1] Suspected Fragment Motion, Shear Mechanism [F-h-1] Suspected Fragment Motion, Hinge Mechanism [F-?-1] Suspected Fragment Motion, Unclassifiable [F-n-1] Suspected Fragment Motion, Neither Hinge nor Shear Mechanism [S-a-2] Known Subunit Motion, Involving Allostery [S-n-2] Known Subunit Motion, Not Involving Allostery [S-a-1] Suspected Subunit Motion, Involving Allostery [S-n-1] Suspected Subunit Motion, Not Involving Allostery [F----] Known, Notably Motionless Proteins (fragment) [D----] Known, Notably Motionless Proteins (domain) [S----] Known, Notably Motionless Proteins (subunit) [C----] Complex Motion [N-R-1] Suspected RNA Motion [N-R-2] Known RNA Motion [N-D-1] Suspected DNA Motion [N-D-2] Known DNA Motion
![Page 10: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/10.jpg)
• http://www.molmovdb.org/cgi-bin/motion.cgi?ID=calbind
• http://www.molmovdb.org/cgi-bin/motion.cgi?ID=calbind&graphics=1
Sample entry in Protein motions
![Page 11: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/11.jpg)
Movies
Thousands of morphs of transitions between PDB files, viewable through a Java applet or as MPEG or GIF movies. Most of these are submissions to the Morph Server by database users
![Page 12: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/12.jpg)
• http://www.molmovdb.org/cgi-bin/morph-classic.cgi?ID=34318-16829
• http://www.molmovdb.org/cgi-bin/morph.cgi?ID=63984-22780
Sample entries in Movies
![Page 13: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/13.jpg)
Structural domain
A structural domain of a protein is a self-stabilizing structural element that often folds independently of the rest of the protein chain. Many domains are not unique to the proteins produced by one gene or one gene family but instead appear in a variety of proteins
![Page 14: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/14.jpg)
Hinge vs. shear motion
Hinge motion is characterized by large changes in main-chain dihedral angles occurring at a localized region (a hinge). Hinge motions are similar to rotations around an articulated joint and therefore can be very large. They usually involve a small number of residues, since even one bond can provide the required rotational freedom.
• Shear motions are very limited and involve large number of residues.
![Page 15: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/15.jpg)
Example of hinge motion: calmoduline
Large-scale movement of calmodulin involving splitting of one long helix. The total rotation of one domain relative to the other is upwards of 150 degrees.
![Page 16: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/16.jpg)
Morph serverIssues Morph server steps
Get start and end configuration Searches for homolog pairs
Make them compatible Homogenizes input PDB files into a consistent format
Find flexible regions Uses homogenized structures to perform a number of additional analyses (hinge location)
Obtain motion Uses adiabatic mapping to interpolate PDB files
Visualize output Allows visualization of interpolated structures in a variety of movie formats
Quantitatively measure output Calculates statistics
![Page 17: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/17.jpg)
Getting start and end configuration
Automated search in SCOP, PDB, etc
Submitted
Manual
Automatic
>1200 user submitted morphs
~200manually classified motions
>14000 automatically classified motions
As of 2003
![Page 18: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/18.jpg)
Making input homogenous
• Most of the truly novel functionality of the server
• Establish equivalence of sequences: alignment (AMPS for similar proteins, structural alignment for distant proteins)
![Page 19: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/19.jpg)
Finding hinges
• Construct a search window of 24 residues and examine each position along peptide backbone in the window. If one half in the window belongs to one domain and the other part belongs to another domain, a hinge is detected.
• If hinges are not found along the backbone, a window is reduced by two and a scan is repeated. After a scan was performed 5 times and no hinges were detected, a failure is reported.
![Page 20: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/20.jpg)
A stand-alone application Hinge master implements several techniques to efficiently spot hinges.
find hingesaccess results
Finding hinges
![Page 21: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/21.jpg)
Interpolation: adiabatic mapping
The morph server attempts to describe protein motions as a rigid-body rotation of a small “core” relative to a larger one, using a set of hinges. To ensure all statistics between any two motions are directly comparable, the motion is placed in a standardized coordinate system.
A pathway interpolation is produced by two principal methods:•Straight Cartesian interpolation. The difference in each atomic coordinate (between the known endpoint structures) is calculated and then divided into a number of evenly spaced steps.
•Adiabatic mapping. Energy minimization is added after each interpolation step. This procedure produces interpolated frames with much more realistic geometry.
![Page 22: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/22.jpg)
Visual rendering
Interpolation produces a set of .pdb files that can be used to produce a custom movie
A movie is created on-the-fly:• a PDF file containing individual frames• MultiGif, Quicktime, MPEG with 2D movie• a VRML 3D movie (requires a plugin)
![Page 23: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/23.jpg)
Statistics
• Maximum C alpha displacement, rotation angle in degrees around putative hinge regions and other parameters
• The statistics are detailed enough to perform automatic preliminary classification of the motion
![Page 24: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/24.jpg)
![Page 25: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/25.jpg)
New multichain morph server
• http://molmovdb.org/cgi-bin/beta.cgi• FRODA lite option added, allowing to
invoke directed dynamics with default parameters
• Hydrogen bonds are not considered, adding protons is not required
• Paths produced by FRODA avoid sterically impossible trajectories
![Page 26: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/26.jpg)
![Page 27: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/27.jpg)
Sample morph
Initial file and final result of FRODAsimulation from previous class were
fed to beta serverdirected motion of barnase
![Page 28: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/28.jpg)
Alternatives
• RigiMol: • Identifies rigid or semi-rigid structural domains. • Displays RMSD, rotation, and translation statistics for the
domains. • Generates interpolated coordinates that effectively "morph"
between the structures. • Outputs standard PDB files to be used for visualization
• LSQMAN: Structural alignment program that does simple morphing using Cartesian or "internal" coordinates.
• Indie server at the NIH. Similar to the Morph Server, but uses linear interpolation and requires the submitted files to have the same sequence.
• DynDom Performs detailed structural comparisons similar to the statistics from morph server. This has a database of motions as well.
![Page 29: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/29.jpg)
Questionable elements
• Every user is free to enter data to MolMovDB
• The system cannot accommodate all types of motions
• Quality of a morph• Quantitative measure
![Page 30: MolMovDB: Database of molecular movements Anastasia Kurdia](https://reader034.vdocuments.us/reader034/viewer/2022051621/5697bfc71a28abf838ca7ad8/html5/thumbnails/30.jpg)
References
• The Database of Macromolecular Motions: new features added at the decade mark. S Flores, N Echols, D Milburn, B Hespenheide, K Keating, J Lu, S Wells, EZ Yu, M Thorpe, M Gerstein (2006) Nucleic Acids Res 34: D296-301.
• The morph server: a standardized system for analyzing and visualizing macromolecular motions in a database framework. WG Krebs, M Gerstein (2000) Nucleic Acids Res 28: 1665-75.
• Wells S., Menor S., Hespenheide B.M and Thorpe M.F. (2005) Constrained Geometric Simulation of Diffusive Motion in Proteins. Physical Biology 2, S127-S136.
• The Yale Morph Server (http://molmovdb.org)
• http://www.public.asu.edu/~frasch/molecular_simulations.htm