Changes between Initial Version and Version 1 of Grant/emplan

Timestamp:

Mar 8, 2011, 1:50:41 PM (15 years ago)

Author:

goddard

Comment:

--

Grant/emplan

@@ +1 @@
+{{{
+#!html
+
+<h1>
+Plans for Electron Microscopy and Molecular Assemblies
+</h1>
+
+<p>
+Tom Goddard<br>
+December 3, 2010.
+</p>
+
+<p>
+Possible projects related to electron microscopy (EM) and molecular assemblies
+for RBVI next NCRR 5-year grant proposal to be submited in May 2011.
+</p>
+
+<p>
+Will talk about 10 project ideas that fall in 2 broad categories:
+</p>
+
+<ul>
+<li>Dissemination: Communicating Analysis Results and Analysis Methods
+<li>Technology: Advances in Visualization and Analysis Methods
+</ul>
+
+<h2>
+Conflicting goals: Impact, Fun, Fundable
+</h2>
+
+<ul>
+<li>Dissemination projects will have higher impact than technology projects
+(short term and long term).
+In electron microscopy / molecular assembly research community
+technology is abundant, know-how and data is scarce.
+<li>It is more fun to work on technology projects.
+<li>Grant reviewers are more impressed by technology projects.
+</ul>
+
+<h2>
+List of Project Ideas
+</h2>
+
+<p><b>
+Dissemination: Communicating Analysis Results and Analysis Methods
+</b></p>
+
+<ul>
+<li>Enable researchers to publish their models, analysis and data on the web
+such that other researchers can build on their work (computationally useful data).
+Map symmetry, segmentations, geometric models (chromatin), operational file
+formats, EMDB/ViPERdb/PDB/CCDB collaboration, web 2.0, lab notebook, 3d browser
+display (WebGL).
+<li>Extend the community of Chimera developers. Programmer documentation,
+simpler APIs, training through collaborations and workshops.
+<li>Video documentation for Chimera usage, task oriented. Currently even
+advanced Chimera users know little.
+</ul>
+
+<p><b>
+Technology: Advances in Visualization and Analysis Methods
+</b></p>
+
+<ul>
+<li>High performance computing: e.g. multi-threading, instancing,
+large atomic models, gpu computing, hdf5 files.
+<li>Continuous and direct mouse interaction (mouse modes):
+e.g. oblique or spherical map slicing, molecule normal modes,
+tiling volume slices, movement with clash detection.
+<li>Comparing large numbers of objects: e.g. conformations from BLAST pdb,
+interfaces between virus proteins, bacteria in termite gut, enzymes binding sites
+(SFLD), alternative fits of molecules in maps.
+</ul>
+
+<ul>
+<li>Coarse grain models.
+<li>Animation.
+<li>SAXS suite of tools.
+<li>High resolution (3-4 Angstrom) EM model building.
+</ul>
+
+<h2>Web presentation of models, analysis and data</h2>
+
+<p>
+Enable users to easily create web pages showing computer readable 3d data
+and analysis and models and interactive 3d renderings.
+Establish and document operational file formats
+(hdf5) to represent volume symmetry, segmentations, coarse grain models, ...,
+that can be adopted by public databases EMDB, ViPERdb, PDB, CCDB.
+</p>
+
+<p><b>Opportunity</b>:</p>
+
+<p>
+EM and molecular assemblies data and analysis is
+95% lost -- only literature publication (pictures and words) of
+results.  Computer readable results are not available except by
+personal request to the lab.  Few EM maps, molecular models, symmetry
+parameters, sequence alignments, SAXS profiles, lists of interacting
+residues, ... are put into public archives.  This stymies the whole
+research community effort to build computational understanding of
+molecular machines, cells, microbial communities.  The build-up of
+computational knowledge from past decades of work is small at EM
+resolutions compared to what has been achieved at finer levels:
+proteins and sequences (PDB and seq databases).
+</p>
+
+<p><b>Possible Products</b>:</p>
+
+<ul>
+<li><b>Multimedia notebook.</b>  Make Chimera able to export directly
+to HTML at user request.  Can append to an html project work log scene
+images, spin animation, 3d model (WebGL), links to Chimera session,
+data files (PDB, map, sequence alignment, list of interface residues),
+measured values (distances, angles, RMSD, surface area, symmetry
+parameters...), user text notes.  Output could be private record of
+data analysis for researcher, would aid creating journal manuscript,
+or can be made public -- web 2.0 style decentralized data publication.
+
+<li><b>File formats for public databases.</b> EMDB/ViPERdb/PDB/CCDB
+can't produce the software that makes data easily accessible. This
+makes it hard for them to establish useful file formats. Analysis
+software should define the file formats. Our strong connections with
+the database sites (EMDB/ViPERdb/PDB/CCDB) can be used to promote
+adoption of our useful file formats for data and analysis results.
+Will require documenting and more careful design of map, segmentation,
+marker set file formats.  An example where software has defined the
+format of analysis results is standard xray data quality report
+(reflections, completeness, R-factor).
+
+<li><b>Data exchange between software.</b>
+Web data publication is most useful if many software packages can read
+the published files.  So Chimera formats (hdf5 maps, segmentations,
+xml markers, symmetry operators, measurements) will have most value if
+other software developers add support to read those.  We know many of
+the software developers in EM / molecular assemblies
+(EMAN/IMOD/Situs/Spider/BSOFT) and can collaborate to add support for our
+publication formats in those packages.
+
+<li><b>Coarse grain model schema and formats.</b>  There are not
+standards for representing coarse grain models, e.g. nuclear pore
+architecture (Frank Albers), chromatin folding (Davide Bau).
+Geometric models using spheres, ellipsoids, tubes, and hierarchy for
+different levels of detail.  Andrej Sali wants to solve this.  Need a
+publishable format.  Chimera marker set XML can be enhanced.
+Computable coarse grain models shared on the web would be innovative.
+
+</ul>
+
+<h2>Chimera Programmer Community</h2>
+
+<p>
+Extend the community of Chimera developers.
+Create programmer documentation,
+simpler APIs, training through collaborations and workshops.
+</p>
+
+<p><b>Opportunity</b>:</p>
+<p>
+Chimera contains many libraries to analyze volume data, molecules and
+assemblies. This is the powerful toolkit I use day-to-day to quickly build
+new analysis capabilities for collaborators.  Ability to write a page or
+two of Python code greatly extends the analysis capabilities of Chimera.
+Programming by users can multiply the value of our core Chimera
+libraries many-fold and extend their lifetime, and avoid others reimplementing
+the same capabilities (e.g. Gorgon, V3D, UROX).
+</p>
+
+<p><b>Possible Products</b>:</p>
+
+<ul>
+<li>Documented well-designed programming interfaces to Chimera modules.
+<li>SciPy module for volume data.
+<li>Programming workshops and collaborator programming training.
+</ul>
+
+<h2>Video Documentation</h2>
+
+<p>
+Screen-capture videos showing how to do common analysis tasks with Chimera.
+Currently even advanced users know little about Chimera.
+</p>
+
+<p><b>Opportunity</b>:</p>
+<p>Most people who have used Chimera hundreds of
+times know only 1/4 of the capabilities they could productively use. I
+see this several times per week.  (Yesterday's example Jiang Zhu, NIH,
+modeling proteins, uses Chimera for volumes, Grasp2 for multiple
+sequence alignments.)  Video how-to documentation can greatly reduce
+the barrier to learning advanced Chimera techniques. Easy to follow,
+no missing steps, shows both how and what can be done.
+</p>
+
+<p><b>Possible Products</b>:</p>
+<ul>
+<li>Video demonstrations showing perhaps 100 common Chimera work-flows.
+My current 12 videos range from 5 to 8 minutes and each includes basic,
+intermediate, and advanced techniques.
+<li>Document common analysis protocols.  Guide to what types of analysis are
+sensible with given data types.  Graduate student researchers often struggle
+with this.
+</ul>
+
+
+<h2>High performance computing</h2>
+
+<p>
+High performance computing: e.g. multi-threading, instancing,
+large atomic models, gpu computing, hdf5 files.
+</p>
+
+<p><b>Opportunity</b>:</p>
+<p>
+The most widely cited Chimera volume capability is fitting a molecule in
+a density map.  Dozens of programs do this.  Our unique advantage is the fit
+is done in one second.  This allows trying many possibilities.  One of the
+most common reasons verbally given for using Chimera for volume display is
+"It loads my very large map, and other programs choke".  Analysis algorithm
+literature focuses almost entirely on quality of results, not speed.  But
+in practice, so much goes wrong in analysis that speed to allow many
+alternate analysis attempts proves more important to whether high quality
+results are achieved.  Where long-running calculations fail to find
+the right answer, many refined quick analysis tries with human inspection 
+can often produce the right answer.
+</p>
+
+<p><b>Possible Products</b>:</p>
+<ul>
+<li>Multi-threaded molecule in map fitting, allows global rotational search.
+<li>Graphical copies ("instancing") for fast and memory efficient display
+of multimeric assemblies and symmetric density maps.
+<li>Memory efficient molecules.  This is our current bottleneck for analysis
+of molecular assemblies (2 Kbytes/atom).
+<li>OpenGL programs for 10x faster molecule display.  Allows for example
+animating motions when examining molecule fitting alternatives (needs 30 frames
+per second, only possible on small systems now).
+<li>HDF5 map files containing subsampled copies of maps.
+<li>Virus map symmetry compression.  60x savings on 1 Gbyte maps.
+<li>Fourier coefficient map representation for fast interactive changes
+in displayed resolution.
+<li>Fast transparent surface rendering.
+<li>Fast morph calculation, for animating model comparisons without user
+separately computing morphs.
+<li>OpenCL GPU computing.
+</ul>
+
+<h2>Interactive mouse modes</h2>
+
+<p>
+Continuous and direct mouse interaction (mouse modes).
+</p>
+
+<p><b>Opportunity</b>:</p>
+<p>
+Continuous hand/eye interaction using mouse dragging is highly
+valuable in analysis.  Most obvious example is rotating a model using
+a mouse drag.  The advantage 30 frame/sec continuous hand control
+becomes very apparent when compared to only being able to change view
+direction with a typed command (as in some older software).
+Translating, zooming, volume contour level adjustment, rotamer bond
+rotation, clip plane positioning, hand fitting, volume cropping,
+molecular dynamics playback, volume morphing are all powerful data
+exploration methods in Chimera.  Many more are not available in
+Chimera.
+</p>
+
+<p><b>Possible Products</b>:</p>
+<ul>
+<li>Mouse mode interface (like paint program), that allows user to
+quickly learn about all continuous interaction modes.
+<li>Allow all continuous interaction using drags in graphics window
+instead of slider in a different window.  Eliminates cumbersome window switches.
+<li>Context sensitive mouse dragging -- where you click in graphics window matters.
+<li>Segmenting volume data using drags to continuously grow regions.
+<li>Mouse wheel flipping volume planes.
+<li>Volume smoothing with degree of smoothing continuous control.
+<li>Spherical virus slices with continuous radius control.
+<li>Oblique slices of volumes with 3d volume shown for context.
+<li>Volume slice tiling (like Mac Expose for tiling windows).
+<li>Continuous atom zone distance variation.
+<li>Steric repulsion when hand fitting.
+<li>Real-time molecular dynamics on small regions during hand motion
+of ligand, or bond rotation.
+<li>Molecule normal animation with hand amplitude control.
+</ul>
+
+<h2>Many Model Comparitive Analysis</h2>
+
+<p>
+Tools to compare large numbers of objects: e.g. conformations from BLAST pdb,
+interfaces between virus proteins, bacteria in termite gut,
+enzymes binding sites (SFLD), alternative fits of molecules in maps.
+</p>
+
+<p><b>Opportunity</b>:</p>
+<p>
+Researchers often compares dozens of homologous structures,
+alternate map fits, segmented volume regions, binding interfaces.
+I commonly see Chimera user's with 10 - 30 open models.
+As biology research accumulates more models, analysis of many
+models becomes as important as the one-at-a-time analysis that
+Chimera, designed in a more data poor era, focuses on.  Working
+with many models becomes too time consuming and tedious to be feasible
+without multi-model analysis tools.  The Chimera View Dock tool is
+a successful example of multi-model analysis.
+</p>
+
+<p><b>Possible Products</b>:</p>
+<ul>
+<li>List all unique binding interfaces in molecular assemblies, e.g.
+virus capsid.  Animate motion to any interface with only contact residues
+shown.
+<li>Allow inspection of dozens of molecule in map fit alternatives,
+for example, animating from one to next with each scroll wheel click.
+Simultaneous text display of goodness-of-fit values.
+<li>Align and average together similar marked objects in EM tomography.
+This is becoming a prominent technique called subtomogram averaging.
+<li>Provide morphing capability between large sets of related structures
+ordered to show principle differences.
+<li>Show all BLAST PDB models with scroll-wheel to show each aligned to
+reference.  And with background prefetch.
+</ul>
+
+<h2>Coarse grain models</h2>
+
+<p><b>Opportunity</b>:</p>
+<p>
+No one has established even a simple common representation for models
+at lower than atomic resolution.  A simple framework supporting
+geometric models: spheres, ellipsoids, tubes, connections, coloring,
+hierarchy, and exchange file format would allow sharing models of very
+interesting biology.  For example, Davide Bau visited this week and
+showed chromatin model, 50 Kbases of DNA adopts unique shapes during
+transcription and when inactive (Nature Struct Biol, out next week).
+He used Chimera volume tracer.
+Sali lab IMP collaboration.  Auer lab cellular structures collaboration.
+This may be a subproject of web data publication.
+</p>
+
+<p><b>Possible Products</b>:</p>
+<ul>
+<li>Make a simple geometric model exchange format that Chimera, IMP, and
+possibly a few other pertinent programs will read and write.
+</ul>
+
+<h2>Stereo Animation</h2>
+
+<p><b>Opportunity</b>:</p>
+3d consumer computer displays and televisions appear to just be taking
+off.  ESPN 3D offers 3d sports broadcasts. Stereo animation may be attractive
+for web data publication.
+</p>
+
+<p><b>Possible Products</b>:</p>
+<ul>
+<li>Export video in stereo formats, YouTube, BluRay.  Study if any web
+browser sequential stereo technology exists.
+<li>Provide continuous depth of field control in keyframe animation.
+</ul>
+
+<h2>SAXS suite of tools</h2>
+
+<p><b>Opportunity</b>:</p>
+<p>
+SAXS data and model visualization I think is an uncolonized niche.
+Standard molecular viewers used with little specialized support.
+Would be possible to make Chimera the standard SAXS visualization software
+(similar to current our monopoly on single-particle EM volume display).
+Don't currently have experimental collaborators (Sali lab methods devel), but
+have talked with Alex Shkumatov in Dmitri Svergun lab -- world leader in SAXS
+computation analysis.
+</p>
+
+<p><b>Possible Products</b>:</p>
+<ul>
+<li>Display volume envelopes derived from SAXS profiles using third party
+computation tools (Svergun lab).
+<li>Handle conformational ensemble fitting to SAXS profiles (Nick Ulyanov
+collaboration).
+<li>Optimize speed of existing SAXS profile calculation (OpenCL GPU computing?)
+for interactive exploration of SAXS fits.
+</ul>
+
+<h2>High resolution EM modeling</h2>
+
+<p>
+High resolution (3-4 Angstrom) EM model building.
+</p>
+
+<p><b>Opportunity</b>:</p>
+<p>
+Single particle EM maps in the 3 to 4 Angstrom resolution range for viruses
+are becoming common.  This is another opportunity to monopolize software for
+an emerging subfield.  I formerly thought existing low-resolution xray model
+building tools would be used for this data.  It appears a new generation of
+model building software is needed.  Matt Baker in collaboration with U.
+Washington computer science dept is developing Gorgon visualization and
+model building from scratch, for 2 years.  It might be disruptive to compete
+with that project.  Also it is a very hard problem, perhaps requiring
+more resources than we can give it.  Gorgon is unlikely to succeed for lack
+of man-power.
+</p>
+
+<p><b>Possible Products</b>:</p>
+<ul>
+<li>Build protein backbones in 3-4 Angstrom maps.  Place side chains where
+possible.
+<li>Possibly some existing xray automated model building system could be
+integrated into Chimera.  Needs research.
+<li>Methods to represent quality of fit.  EM model validation is a very
+active research problem.
+</ul>
+
+<h2>Do these ideas require replacing Chimera?</h2>
+
+<p>
+I favor large-scale incremental software changes, instead of starting over,
+but we have never made such changes (can't shake OTF, wrappy,
+Tk, fixed function OpenGL, extend atom specs to surfaces, memory efficient
+molecules, abstract models are molecules).  Our practised accretion method
+with no major changes offers good stability for outside developers
+but we don't have many of those for other reasons.
+</p>
+
+<p>
+Developing a next-generation Chimera 2 while maintaining Chimera 1 is the
+pattern we followed with the MidasPlus to Chimera transition, but it required
+more than 5 years to get the next-generation code into initial distribution.
+Chimera 2 could leverage much of the existing volume C++ code.
+</p>
+
+}}}