10x40k Crunch Scott Dixon Jeff Blaney Dave Weininger

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What?

• 40,000 small molecules docked to 10 proteins using DockIt with results stored in a standard Thor/Merlin database.

• DockIt: fast distance-geometry-based docking
  • Robust program designed for production work
  • Analytical DOCK solution
  • Fastest distance-geometry-based docking program yet
  • Three scoring functions: DOCK, PMF, PLP
  • New Metaphorics product

• 10 proteins
  • One protein, 1hpv, was selected "on purpose"
  • Others selected randomly from ~150 known protein-ligand structures
  • 1add 1ela 1hpv 1hyt 1rbp 1rds 1swd 2cbr 3cla 4hvp
  • Small & large, simple & complex, well-known & obscure, one pair
  • All observed bound to ligands (which were also docked)

• 40,000 small molecules from bioscr99sc
  • Database of diverse compounds intended for screening
  • Well-formed data, e.g., isomers, salt data
  • Plated samples are available from InterBioscreen
  • Freely available as Thor database

• Computation
  • 10 by 40,000 by 100 trials each makes 40,000,000 dockings
  • Done on 240/256 R12000 processor SGI/Cray supercomputer
  • CEX used for communication between programs

• Informatics
  • Results as CEX objects converted to Thor datatrees
  • Concensus pick: ~400,000 conformations
  • Thor: $D3D-rooted subtrees contain scores, rms, etc.
  • Merlin: SMILES/conformation rows, 3-D data not in pool
  • Rasmol: widely used, free visualization program, local "expert"

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Why?

• How many structures/dockings does it take to generate interesting results? Is 40,000 not enough, enough, more than enough?

• Are some proteins very specific and some promiscuous, or more-or-less the same?

• Are some small molecules very specific and some promiscuous, or more-or-less the same?

• Do current (faddish?) scoring functions produce sensible results?

• Is RMS a sensible gold standard?

• Does consensus scoring make sense?

• Does DockIt/docking eliminate obvious losers?

• Does DockIt/docking find known binders?

• Can "normal" informatics be wrapped around docking data?

• Are generic communication (CEX, XML) protocols suitable for production work?

• Is DockIt ready for prime-time?

• Do you need DockIt in your shop?

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When? How?

• Project started less than a month ago, done in a couple weeks!

• Started with a close-to-production CEX-talking DockIt, production Daylight small-molecule database and DBMS software, etc.

• Would have taken a long time on our machines (45 days / many months). Even using local compute resources (NCGR) would have taken ~9 days, we would have been hard-pressed to get it onto CD-ROM by MUG.

• SGI generously provided time on a brand new (-1 week old) 256 R12000 processor machine. Compute time using ~240 of the CPUs was less than 24 hours.

• Access to the machine needed to be via private SGI network, so Scott camped out at the SGI sales office in Portland and got it done.

• The result set was ~54 GB. Getting the results backed out and transferred was as difficult and time-consuming as everything else combined.

• Reduction of the data to Thor/Merlin database format was relatively easy: done in a day.

• CD-ROMs are available now.

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Results

• Database contains:

  • 10 proteins as bound to ligands

  • 10 ligands as bound to proteins

  • lowest RMS docking of 10 ligands to their proteins

  • consensus docking of 38,123 small molecules to each of 10 proteins

  • SMILES-rooted data:
    • name
    • fingerprint
    • heavy atom count

  • conformation-rooted data:
    • RMS for bindings
    • DOCK, PMF and PLP scores for dockings
    • docking consensus score (and ranks)
    • docked-to and bound-to IDs

• m4x10x40k database contents:

  • 38,143 SMILES-rooted datatrees, 10 are proteins: 10 are observed ligands, the rest (38,123) are from bioscr99sc.

  • 381,113 conformation-rooted subtrees: 20 are bindings, the rest (381,093) are dockings,

  • 381,103 sets of DOCK, PMF, PLP & consensus scores

• m4x10x40k database sizes:

  size, MB	description
  205.9	m4x10x40k.DP, biggest file
  235.0	all database files
  65.3	merlin pool (3,620,250 dataitems)
  72.9	merlin total, including overhead

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Preliminary conclusions

• Docking informatics is definitely doable.

  • However, this represents a big change from how things are currently done.

• Handling 10's of GB's of data is work, but not "rocket science".

  • Modern disks have enough capacity.

• Daylight DBMS works fine with proteins.

  • Proteins are just big molecules!
    (Most are not really so big, at that.)

  • Almost no changes were needed to the Thor/Merlin system.

• CEX makes such informatics possible.

  • CEX could be faster

  • XML might work if it came of age

  • Pushing around 40,000,000 PDBs would not have been reasonable

• DockIt is ready for production

  • DockIt definitely cranks.

  • Scale up is not a factor: large-scale performance is within a few percent of predictions.

  • Can expect to complete large jobs w/o crashes, blowups, etc.

  • Automated sphere generation (sphinx) and refinement (sublime) are 90% but not 100% ... yet.

  • We still have the choice between best (with H's) or fast (without H's), but not "best and fast" at the same time.

• Lots of interesting dockings crop up

  • Could these strange and wonderful scaffolds really work?

• The current crop of scoring functions aren't wonderful.

  • Size bias. Surprisingly expensive. False positives.

  • Between-molecule scoring comparisons are non-intuitive.

  • The three scoring functions provided with DockIt are very different from each other. In so far as they represent the current world-range in scoring, these three are about as good as one can do.

  • Between-molecule consensus scoring has practical (rather than theoretical) merit.

  • Conformational consensus scoring seems to work well (e.g., among 100 docked conformations of the same molecule). However, that's not what most people want to know.

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Acknowledgements

• Tom Magdziarz, SGI, Mountain View
• David Zirl, SGI, Mountain View
• Tim Tomasi, SGI, Portland
• Bill Durch, SGI, Chippewa Falls
• Pete Wargo, NCGR, Santa Fe
• Metaphorics Krewe, Santa Fe & Mission Viejo

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