2023-10-27 Flatiron Institute / Michael Shirts Meeting notes

 Date

Oct 27, 2023

 Participants

  • @James Eastwood

  • @Michael Shirts

  • Vikram Mulligan (FI)

  • Doug Renfrew (FI)

  • Bargeen Turzo (FI)

 Goals

  • Get an overview of FI’s interest in foldamers and the Masala software suite

  • Sketch out technical needs for OpenFF integration into Masala

  • Identify areas for collaboration on foldamer design and simulation

 Discussion topics

Time

Item

Presenter

Notes

Time

Item

Presenter

Notes

 

Scientific / Technical Presentation

Vikram Mulligan

  • Previous work: Designing peptides of mixed L/D amino acids with unnatural folds

  • Macrocycles

    • Macrocycles designed to target the Wuhan variant of SARS-CoV-2 spike glycoprotein

      • micromolar affinity

      • Redesigned to target Omicron

  • Current software limitations

    • Accuracy

    • Generality and extensibility

    • Tractability and efficiency

  • Rosetta is a kinematics engine and a scoring engine

    • That is very good at building protocols

  • Rosetta is very good at solving the rotamer optimization problem

    • This is how we do design

  • Predicted fold propensity (estimated dG of folding) correlated well with IC50

  • Mike Gilson: Mining Minima

  • Enhancing Rosetta’s energy calculations with quantum chemistry

  • Limitations of Rosetta as a platform for future science

    • MPI-parallel but not GPU-parallel

    • “Pose” data structure is optimized for side chain optimization, relaxation, and backbone sampling

      • Ideally we could convert data structures for different tasks

    • Rosetta is a monolith (software engineering perspective)

  • Designing and building the Masala software suite

    • Usable as stand-alone or robust library

    • Free and open source successor to Rosetta under development at Flatiron

      • aGPLv3

    • Structured to take advantage of massively parallel CPU or GPU

      • Thread manager

      • Scales nicely up to hundreds of CPU cores

    • Versatile plugin architecture

      • Internal library

      • API layer

      • Plugins

      • User interfaces

    • API layer is built from JSON API description

      • Allows regression testing of API description

    • Special types of Masala plugins

      • Engines

      • Data Representations

      • These are usually handled in one plugin

        • define a new data representation optimized for a given engine

        • Convert data structure

        • pass it to engine

        • do the (highly efficient) work

        • Convert back to standard data structure

        • pass back to Masala internals

    • Using Masala to implement packing on quantum computers

  • Hope to implement translator to and from OpenFF to set up force fields

    • Option 1: Implement internal Masala representation of molecule and implement our own machinery to parameterize it with force field from offxml

    • Option 2: Use OpenFF’s implementation (toolkit) to parameterize the system

    • Option 3: Use Interchange to output in a different format









 Action items

Create slack channels for #flatiron-collaboration (private) and #generic-polymers

 Decisions