An Introduction to Molecular

Visualization with UCSF

Chimera
John “Scooter” Morris, Ph.D.
[email protected]
University of California, San Francisco

1
 Introductions
• About me
– John “Scooter” Morris:
• RBVI Executive Director
• Adjunct Professor, Department of Pharmaceutical
Chemistry, UCSF
• 19 years in pharmaceutical industry (Genentech)
• 11 years at RBVI

2
 Introductions
• Who are you?
– Biologists?
– Chemists?
– Bioinformaticists?
– Computer Scientists?
– Other Computational Sciences?
– Other?

3
 Materials
• Handouts
• Downloads
– Chimera 1.10.1
– Data files

4
 Agenda
• Demo
– …while Chimera installs.
• Introduction to UCSF Chimera
– Basic principals
• Hands on Tutorial
• Q&A
• Glimpse of the future (Chimera2)

5
 Demo
• HIV Capsid

6
 Molecular Visualization
• Data sources
• Representations
• Manipulations
• Analysis
• Modeling

7
 Definitions
• modeling (model):
Function: verb
transitive verb
1 : to plan or form after a pattern : SHAPE
3 b : to produce a representation or simulation of <using a computer
to model a problem>
4 : to construct or fashion in imitation of a particular model <modeled
its constitution on that of the United States>
intransitive verb
1 : to design or imitate forms : make a pattern <enjoys modeling in
clay>
• visualization:
Function: noun
1 : formation of mental visual images
2 : the act or process of interpreting in visual terms or of putting into
visible form

8
 Data sources
• Structure determinatation
– Xray crystallography
– NMR
– EM/Cryo EM
– Models (ab initio, homology)
• Volumetric data
– EM/Cryo EM
– Electron density
– Light microscopy
• Non-structural data sources
– Sequence data
– Pathway data
– Interaction data
– Expression data

9
 Data sources
• Structure repositories
– Protein Databank: http://www.rcsb.org/
– Nucleic Acid Database (NDB): http://ndbserver.rutgers.edu/
– Structural Classification of Proteins (SCOP):
http://scop.mrc-lmb.cam.ac.uk/scop/
– ModBase: http://modbase.compbio.ucsf.edu/
– Cambridge Structural Database (CSD):
http://www.ccdc.cam.ac.uk/products/csd/
– VIPER EM Database: http://mmtsb1.scripps.edu/emdb/
– EM Database: http://www.ebi.ac.uk/msd-srv/emsearch/index.html
– Uppsala Electron Density Server: http://eds.bmc.uu.se/eds/

10
 Representations
• Wire
• (Ball &) stick
• Sphere (VDW)
• Secondary Structure
– Ribbon
– “Pipes & Planks”
• Surfaces
• Specialty
– “Worms”
– Nucleic acids
11
Combining Representations

12
 Other Visual Displays
• Labeling
• Hydrogen bonds
• Geometric objects
• Distances
• Clipping
• Many others
– Chimera Gallery (http://www.cgl.ucsf.edu/chimera/ImageGallery)
– VMD Gallery (http://www.ks.uiuc.edu/Research/vmd/gallery/)
– BALLView (http://www.ball-project.org/Gallery/)
– PyMOL Images (http://pymol.sourceforge.net/pmimag.html)

13
 Animation
• Presentation
– Overcome lack of stereo (provide 3D cues)

14
 Animation
• Presentation
– Overcome lack of stereo (provide 3D cues)
– Demonstrate (possibly) hypothetical
interactions
• Morphing between conformations
• Molecular mechanisms

15
 Animation
• Presentation
– Overcome lack of stereo (provide 3D cues)
– Demonstrate (possibly) hypothetical
interactions
• Morphing between conformations
• Molecular mechanisms
• Analytic
– MD movies
– Scanning multiple structures or conformations

16
 Manipulations
• Selection
• Movement
• Focus
• Zoom
• Changing representations
• Labeling
• Alignment
• Modeling “lite”
– Bond adjustments
– Adding/deleting/changing residues

17
 Modeling
• Homology modeling
– Uses similar molecules of known structure as a template to
derive molecular structure.
• Molecular mechanics
– Models atoms and spheres and bonds as springs
– Non-bonded atoms interact through van der Waals attraction,
steric repulsion, and electrostatic attraction/repulsion
– General goal is to minimize an energy equation (force field)

18
 Modeling
• Molecular dynamics
– Models the motions of a molecular system, including
conformational transitions and local vibrations, using molecular
mechanics force fields
– Takes into account the thermodynamic environment
– May be used to compute both thermodynamic and kinetic
properties
– Result is an ensemble (i.e., a movie) of how the molecule moves
• Quantum (ab initio) modeling
– Structures are solved by approximating the Schrödinger
equation for all particles (nuclei and electrons) in the system.

(see http://cmm.info.nih.gov)
19
 Applications of molecular visualization

• Computational chemistry
– Dynamic molecules
– Molecular interactions
• Microscopy
– Lower resolution, volumetric data
• Genomics
– Sequence-structure-function relationships
• Systems biology
– Broad view across variety of data

20
 Scenarios of use
• Analysis
– Molecular dynamics
– Docking
– Sequence-structure relationships
– Low-resolution representations
• Viruses and large complexes
• Electron microscopy
– Structures in context
• Publication
– High-resolution images
– Animation
21
 Molecular dynamics
• Crystallography determines the
conformation of molecules in crystalline
form
• Molecular mechanics describes the
physics of atomic forces
– Energy minimization finds local minima
– Molecular dynamics (MD) simulates motion of
molecules in solution
– Free energy perturbation computes binding
energy

22
 Docking
• Molecular docking is used to screen ligand
databases to find lead compounds
– Rigid-receptor docking is faster, but assumes
that a single receptor conformation is
sufficient
– Flexible-receptor docking is more realistic, but
requires much more computational resources

23
 Sequence-structure relationships
• There are still many more sequences
available than structures
• Sequence similarity is often used to infer
function
• Structure similarity is critical for
mechanism
• By viewing both sequences and structures
together, we can get a more
comprehensive view

24
 Volumetric Data
• Structural experiments frequently yield
volumetric data
– X-ray crystallography
– Electron microscopy
– Tomography
• Viewing derived molecular structures with
experimental data is useful for:
– Consistency check between derived data and
experimental results
– Fitting modeled structures to experimental
results
25
 Multiscale representations
• Molecular data are available at different
resolutions (scales)
• Viewing structural data at multiple scales
simultaneously provides context
• Example: Virus capsid display
– Take advantage of capsid symmetry
– Showing both shape and component proteins
more useful than either alone

26
 Structures in context
• Protein similarity networks
• Pathways
• Protein interaction networks

• Cytoscape — Chimera integration

27
 Questions?
• Any other scenarios of interest?

28
 Available Tools
• Visualization
– “Full featured” academic packages
• UCSF Chimera (http://chimera.ucsf.edu/)
• PyMOL (http://pymol.sourceforge.net/)
• VMD (http://www.ks.uiuc.edu/Research/vmd/)
– Viewers
• Jmol (http://jmol.sourceforge.net/)
• RasMol/Chime (http://www.openrasmol.org/)
• SwissProt PDB-Viewer (DeepView) (
http://www.expasy.org/spdbv/)
• RCSB Protein Workshop (http://www.rcsb.org/)
29
 Available Tools
• Visualization
– Other useful tools
• Photoshop
• Renderer (POV-Ray or Renderman-based)
• Animation package (Maya)
• Stereo-capable workstation

30
 Available Tools
• Analytical tools (partial list)
– PROCHECK (http://www.biochem.ucl.ac.uk/~roman/procheck/)
– Structure-Function Linkage Database (http://sfld.rbvi.ucsf.edu/)
– ExPASy (http://www.expasy.org/)

• Modeling tools
– Amber (http://amber.scripps.edu/)
– Charmm (http://www.charmm.org/)
– NAMD (http://www.ks.uiuc.edu/Research/namd/)
– Gaussian (http://www.gaussian.com/)
– ModBase (http://modbase.compbio.ucsf.edu/)
– Modeller (http://www.salilab.org/modeller/)
– DOCK (http://dock.compbio.ucsf.edu/)
– Many, many more (see http://cmm.info.nih.gov/)
31
 Comparison of Visualization Packages

• Viewers
– Jmol
• best-in-class viewer
• web enabled
• scriptable
• input only
• compatible with RasMol scripts
• limited analytical capabilities
– mostly through Javascript wrappers

32
 Comparison of Visualization Packages

• “Full Featured”
– PyMol
• best-in-class for peptidometics, speed
• single-screen interface (+command line)
• extensible
• some modeling capabilities
• good publication tools (built-in ray tracer)
• scriptable

33
 Comparison of Visualization Packages

– VMD
• best-in-class for MD (integrated with NAMD) and
other analysis tools
• scriptable
• excellent stereo capabilities
• embedded ray tracer (Tachyon)
• extensible
– now supports Python, previously was only TCL/TK

34
 Comparison of Visualization Packages
– Chimera
• best-in-class for visualizing very large structures
– multiscale extension
– volume viewer
• focus on extensibility, broad functionality
• primarily analytical interface
• familiar GUI interface (+command line)
• scriptable
• reasonable tools for publication & presentation
• embedded ray tracer (POV-Ray)
• excellent sequence/structure capabilities
• reasonable interface to modeling programs
35
 Comparison of Visualization Packages

• Caveats
– Our focus is primarily on Chimera
– We are not users of other packages
– There is no “best” package for everything (in our
opinion)
– YMMV (Your Mileage May Vary)
• What we think is easy, you may think is hard
• What we think is hard, you may think is easy
– Choosing the best package for you
• Does what you need
• Good documentation
• Good support (either local or from the authors)

36
 UCSF Chimera
• Target audience
– Scientists who need to analyze and model
molecular systems in some detail
– Scientists who want to develop new analytical
methods
– Scientists or educators who wish to
communicate biological concepts visually
• Organization
– Core features
– Additional tools
37
 Chimera Core Features
• Concepts
– Graphical manipulation
– Chemical knowledge
• Hierarchy: Model→Chain→Residue→Atom
• Attributes available at model, residue, and atom
levels
– Selection - Action
– GUI/Command-line equivalence
• For core, not necessarily extensions

38
 Core Features (cont.)
• Using the mouse
– Pointer over atom
• “Tooltip” with atom and residue information
– Left-button
• X-Y Rotation (on virtual sphere)
• Z Rotation (outside of virtual sphere)
– Middle-button
• X-Y Translation
– Right-button
• Scale
– Control+
• Left-button: select (click or drag)
• Middle-button: Z translation

39
 Core Features (cont.)
• Useful tools
– Side View
• Helps locate model in Z direction
• Provides access to hither-and-yon clipping planes

40
 Core Features (cont.)
• Useful tools
– Side View
• Helps locate model in Z direction
• Provides access to hither-and-yon clipping planes
– Selection Inspector
• Provides information about currently selected atom, residue, and model
(and bond, pseudo-bond, and surface)
• Short-cut to changing representation of selected item

41
 Core Features (cont.)
• Useful tools
– Side View
• Helps locate model in Z direction
• Provides access to hither-and-yon clipping planes
– Selection Inspector
• Provides information about currently selected atom, residue,
and model (and bond, pseudo-bond, and surface)
• Short-cut to changing representation of selected item
– Model Panel
• Access to several attributes and actions of currently open
models
• Allows selective display of models
• Allows selection of models that will respond to mouse motion
(useful to move one model in relation to another)

42
 Core Features (cont.)
• Useful tools
– Side View
• Helps locate model in Z direction
• Provides access to hither-and-yon clipping planes
– Selection Inspector
• Provides information about currently selected atom, residue, and model (and
bond, pseudo-bond, and surface)
• Short-cut to changing representation of selected item
– Model Panel
• Access to several attributes and actions of currently open models
• Allows selective display of models
• Allows selection of models that will respond to mouse motion (useful to
move one model in relation to another)
– Sequence
• Displays sequence of currently loaded structures
• Selection linked to structure
• Can display alignments
• Access to several sequence-related tools: CDD & Uniprot annotations,
BLAST PDB, sequence alignment calculations, modeling
43
 Core Features (cont.)
• Selection methods
– Using mouse
• Control-click and control-drag
• Shift-control-click and shift-control-drag to add to selection
– By atom and residue names and types
– By higher order structure
• e.g., chains, ligands, solvent
– By spatial location
• e.g., within some distance of another selection
– By attribute values
• e.g., temperature factor, occupancy
– Can extend any selection with up-arrow: ↑
– NOTE: by default, if nothing is selected, everything is selected

44
 Core Features (cont.)
• Actions
– Hide/show/delete parts of structure
– Change representations
– Change colors
– Display labels
– Show molecular surfaces
– Focus on parts of interest

45
 Commonly used tools
• Depictions
– Nucleotides
– Rainbow coloring
• Structure analysis
– FindHBond
– Sequence
– Distances
• Utilities
– 2D Labels
– Reply Log
– Movie Recorder

46
 Questions?
• Anything you want to see in particular?

47
 Extending Chimera
• Incorporating user data
• Scripting
• Python extensions

48
 Incorporating user data
• Chimera supports user-defined attributes
for atoms, residues and molecules
• Once defined, these attributes may be
used for selection and rendering using the
“Render by Attribute” extension

49
 Scripting
• Scripting is executing a set of commands
from a file
– Useful for repetitive tasks
– Can serve as documentation
– Available in most visualization packages
• Chimera commands may be read in from a
file or typed directly in the command line
interface
• Chimera “Demo” extension combines
scripting with simple hypertext to create
illustrations
50
Questions?

51
 Chimera Recent Additions
• Modeling
- Rotamers
- Fetch modeled structures from ModBase
- Web service interface to Modeller and IMP
- Web service interface to BLAST
• Animation and illustration
– Movies can now be rendered with POVray
– Scenes and Storyboards
• Volume visualization
– New tools for tomographic data
• Systems biology
– structureViz: links Cytoscape to Chimera

52
 Visualization Directions
• Context
– Environment
– Systems biology
• Complexes
– Protein-protein
– Protein-nucleic acid
– Molecular machinery
• Motion
– Molecular transitions
– Machinery mechanisms
– Conceptual illustration
53
 Visualization Directions
• Data sources
– Web services
– Multiple data types

54
 The End
• Questions?
• Comments?
• Suggestions?

55
 Backup Slides
• Detailed comparison charts

ISMB 2008: Introduction to Molecular Visualization 56

feature Chimera RasMol Jmol 10.2 PyMol 0.99 Deep View VMD 1.8.4 DINO Molmol 2K.
1.2199 2.7.3 3.7 0.9.1 2

PDB I/O I/O I I/O I/O I/O I/O I/O

Mol2 I/O I - I - I/O - I
CIF/mmCIF - I I - - - - -
Web app - PE + - - - - -
sessions + - - + + + - +
color editing + - - + + + - +
transparency + - + + SG SD + -
molecular surfaces + + + + + + DR +
interface surfaces + - - - - + - -
solid clipped surface + + - - - PV + -
arbitrary clipping + - - - - + + -
movable labels 2D - - + - - - +
special nucleic disp + - - + - + + +
geometric objects + - + + - + - +
high-quality images + - - + - - + +
ray-tracing support + + + ++ + + + +
stereo + + + + + ++ + +
multiscale/low-res + - - - - LR - SH
volume isosurfaces ++ - + + + + + +
transparent volumes + - - - - - - -
edit/write vol data + - - - - - - -
auto fit to density + - - - - - - -
measure volume + - - - - - - -

ISMB 2008: Introduction to Molecular Visualization 57

feature Chimera RasMol Jmol 10.2 PyMol 0.99 Deep View VMD 1.8.4 DINO Molmol 2K.
1.2199 2.7.3 3.7 0.9.1 2

atom type ident + - - - - - - -

select AA category + + FG/ST - + + + -
H addition + - - SA SA SM - SR
H-bond ident ++ + FG + + + - +
charge assignment SR - - SR SA SM - SR
ESP calculation ID/DR CL - AP/DR CL/PB AP/DR DR PB
AA rotamer library - - - + + - - -
energy minimization - - - - + NM - -
render by attribute (e.g. ++ + + + + + + +
color bfactor)
user-defined attribs + - - - - - - -
seq align viewer ++ SP SP/ST(I) SP IG SP/IG - -
seq-based match + - - + + - - -
struct-based match + - - SP + + - -
seq align from match + - - - PW + - -
MD playback + - PO + - ++ + PO
view docking results + - - - - - - -

context/balloon help + - + - - - - +

user docs ++ + + OD + + + ++
programming docs + - - - + + - -

extensibility + - + + - + - -
source distrib + + + + - + - +
platforms W/M/U W/M/U W/M/U W/M/U W/M/U W/M/U M/U W/U

ISMB 2008: Introduction to Molecular Visualization 58

I input
O output
- feature not present
+ feature present
++ feature present and comparatively extensive or sophisticated
PE Protein Explorer { #52} is a Web application based on RasMol
SG only surfaces and only on Silicon Graphics
SD “screen door” transparency
DR displays results from other programs
PV non-interactive solid-color clip available via POV ray-tracer
2D arbitrary labels can be created and moved in the plane of the screen
SH only certain shapes (rectilinear boxes, spheres, ellipsoids)
FG via FirstGlance in Jmol (http://firstglance.jmol.org)
ST via STING { #56} (http://www.cbi.cnptia.embrapa.br/SMS/); (I) = Windows/Intel Linux only and only alignments from STING-
related databases
SA residues with topology files in the distribution (standard amino acids and a few others)
SM small structures only
SR residues in the AMBER 94 library { #77} (used in the ff94-ff99 versions of the force field)
ID interface to DelPhi { #75; #76} (obtained separately)
CL Coulomb’s law calculation
PB Poisson-Boltzmann calculation
AP interface to Adaptive Poisson-Boltzmann Solver { #74} (obtained separately)
NM via input to/output from NAMD { #73}
SP STRAP plug-in { #49}, http://www.charite.de/bioinf/strap/ (Java); according to the author, interfacing to RasMol and VMD may
only work on Unix, and only PyMol shows structure superpositions from STRAP (see
http://www.charite.de/bioinf/strap/pymol.html)
IG internally generated alignments
PW pairwise comparisons only; adjusts one sequence relative to one other
PO PDB-format input only
OD out-of-date user manual supplemented with mailing list and volunteer-provided tutorials and wiki
platforms: W Windows, M Macintosh, U Unix

ISMB 2008: Introduction to Molecular Visualization 59

 Backup
RasMol { #53; #54} : http://www.bernstein-plus-sons.com/software/rasmol/
Jmol { #32}: http://jmol.sourceforge.net/
PyMol { #29}: http://pymol.sourceforge.net/
Deep View (Swiss-Pdb Viewer) { #51}:http://ca.expasy.org/spdbv/
VMD { #24}: http://www.ks.uiuc.edu/Research/vmd/
DINO { #55}: http://www.dino3d.org/
Molmol { #48}: http://hugin.ethz.ch/wuthrich/software/molmol/

ISMB 2008: Introduction to Molecular Visualization 60