Work in progress February 6 - March 12, 2025

Tom Goddard
March 13, 2025
Group meeting

Topics

• Structure prediction with Boltz
• Sony and Acer 3D displays
• BlueSky social media

Boltz structure prediction

• Boltz is a structure prediction program derived from AlphaFold 3 with similar accuracy to AF3.
• Predicts assemblies of proteins, DNA, RNA, ligands, ions, solvent.
• Created by PhD candidate Jeremy Wohlwend in the Regina Barzilay lab at MIT.
• Fully open source, MIT license. AlphaFold 3, Chai-1 and other ML structure prediction programs do not provide training code preventing the research community from improving the prediction method.
• bioRxiv preprint

AlphaFold 3 score vs Boltz score for 1508 drugs

Comparison of Boltz to AlphaFold 3 for ligand binding

• Ran Boltz predictions of 1508 FDA approved active ingredients against monkeypox mRNA decapping enzyme E10R.
• Compared Boltz predictions to AlphaFold 3 predictions.
• Boltz and AF3 gave very different confidence scores to the drugs as shown in a scatter plot of ipTM scores.
• None of these FDA compounds are known to bind to this protein, very likely none bind well.
• Boltz and AF3 often give correct ligand poses when predicting ligands known to bind to a target.
  • Boltz gets 40% with RMSD < 2A for CASP 15 ligands.
  • AF3 gets 80% with RMSD < 2A for 427 ligands in PoseBusters benchmark.
• Conclusion: Boltz and AF3 high confidence scores do not imply ligand binding.

Vermurafenib	Droperidol	Bumetanide
When Boltz and AF3 have high ipTM scores, both give same ligand pose. AlphaFold 3 (tan), Boltz-1 (blue)

Boltz on Mac

• Tried Boltz on Mac M2 machine.
• 248 amino acid monkeypox E10R protein with FDA ligands took on average 1 minute compared to 8 seconds on Linux with Nvidia 4090.
• 1 minute prediction time for small protein and ligand is plenty fast.
• Boltz uses PyTorch which has Mac GPU acceleration called Metal Performance Shaders (MPS).
• By comparison E10R prediction (no ligand) using ChimeraX Colabfold server takes 12:22 minutes for 5 predictions or 7 minutes for a single prediction (breakdown 1:00 to install Colabfold, 2:38 download 3.5 GB network, 1:00 MSA, 1:00 start load network, 1:20 per prediction (5x)).

ChimeraX Boltz structure prediction tool

Extremely basic prototype is working on Mac.

• Goal is to put a ChimeraX Boltz structure prediction tool for June release.
• Expect this will be one of the most used features of ChimeraX.
• New capabilities it adds:
  1. Predict structures with ligands and ions and nucleic acids.
  2. Much faster than Colabfold / AlphaFold 2.
  3. Runs on local computer.
  4. Estimates time for each job to plan predictions of large complexes that could take hours.
  5. Allow queueing many jobs to run sequentially and in background.
  6. Easier specification of molecules to predict by using structures opened in ChimeraX.
• Implementation challenges:
  1. Provide one button install of Boltz on local machine (Mac, Windows, Linux).
  2. GUI to flexibly specify proteins, nucleic acids, ligands in various ways is complex.
  3. Video demonstrations of different workflows and Boltz options on YouTube and BlueSky needed.
  4. Boltz uses Colabfold MSA server which is heavily loaded. May want UCSF MSA server.
  5. Boltz needs to read SDF format ligands to easily handle covalent linking, currently only CCD or SMILES.

Sony Spatial Reality 3D display

Paxlovid bound to SARS-CoV-2 main protease

T-cell electron tomography (EMDB 1273)

• Sony Spatial Reality display works without glasses.
• Uses eye tracking and diffraction grating over 4k display to direct different screen pixels to left and right eyes.
• Made web page describing advantages (from Greg Pintilie) and trouble spots.
• Made several OpenXR fixes (ticket #16864).
  • Made mouse scale, translate in z, select, rotate about correct center in OpenXR mode. Previously mouse interactions were not used with OpenXR since VR headsets use hand controllers.
  • Made 3D model position match the initial position on 2D display. This makes sense for a flatpanel display but not for VR headsets where there is no fixed viewing direction.

Acer SpatialLabs 3D display

Acer Model Viewer showing GLTF exported from ChimeraX.

SpatialLabs Eyes stereo camera

• Jane Hsu and Yuli Wang from Acer Taiwan brought Acer SpatialLabs View Pro 27" display to VizVault.
• Phil Cruz joined by Zoom. Eric Pettersen and faculty Joanne Chun, students Jeff Lin and Ryan from UCSF AI and Computational Drug Design program joined in-person.
• Jane demonstrated
  1. ChimeraX displaying molecules using SteamVR.
  2. Acer Model Viewer application showing NIH 3D molecular models (GLTF format).
  3. Hand gestures to z translate (fist), zoom (two hand pinch), rotate (one hand pinch), and show next model (wave).
  4. Acer SpatialLabs Eyes stereo camera (8 Mpixel/eye) rendering to the display (side-by-side video) for Zoom meetings.

ChimeraX OpenXR for Acer SpatialLabs 3D display

• ChimeraX OpenXR is not working, shows only a black screen on the Acer display.
• We are borrowing the display for 3 months to get ChimeraX OpenXR to work with it.
• Using OpenXR will eliminate the need for SteamVR and a Steam account and plugin.
• Debugging shows Acer OpenXR is not providing the eye locations to ChimeraX. I have filed a ticket DS-179 with SpatialLabs developer support.

BlueSky social media

ChimeraX BlueSky web page

• Zach setup ChimeraX BlueSky account several months ago as an alternative to X/Twitter.
• I made 5 posts of new features which brought in about 80 new followers.
• Have just 477 followers vs 7000 on X/Twitter.
• So far have just 6 posts on BlueSky vs 147 on X/Twitter.
• BlueSky has 33 million registered users vs 368 million monthly active users on X/Twitter.
• Plan is to keep posting on BlueSky only to migrate users to this less political platform.