j-wags
commented
4 years ago Hi,
Automated handling of modified amino acids is one of the major items on our roadmap, however it's probably a few months out at least. This is a deceptively difficult area. We will likely take the approach of using the bespoke workflow to re-parameterize the entire AA+PTM molecule, and then merge it into an unmodified protein backbone. However, this will require
1) the bespoke parameterization workflow, which is still under development 2) a OFFXML equivalent of an established protein FF, which is still under development 3) an automated way to build, cap, and un-cap PTM-modified AAs
In the shorter term, it may be possible to do this by manually (or in a semi-automated fashion). I'd think that the trickiest part of doing this by hand would be figuring out how to patch in the bonds, angles, and torsions at the interface of the OpenFF ligand and AMBER protein with reasonable values.
An first pass at an automated solution to this might
- parameterize the protein, as normal
- parameterize a N- and C-terminal-capped AA+PTM molecule, using OpenFF
- create a new openmm system, particle by particle, mirroring the protein system until the modified AA is reached, at which point...
- the original AA is loaded into ParmEd and turned into a networkX graph of parameters, removing a single hydrogen where the PTM attaches (and all parameters involving that hydrogen)
- the AA+PTM molecule is loaded into ParmEd, and turned into a networkX graph of parameters, removing the N- and C-terminal capping groups (and all parameters involving those capping groups)
- a graph isomorphism is run on uncolored versions of both graphs, to get a map of atom indices
- iterate over all the parameters in the un-modified AA graph, and copy them into the modified AA+PTM graph, overwriting the ones that already exist
- add the particles/parameters from the AA+PTM graph to the OpenMM System
- Finish copying the un-modified AAs verbatim into the new OpenMM System
I don't think I'll have time to implement the above algorithm any time soon, but we'd very much appreciate a PR if you're feeling up to the task :-)
DNA2RNA
davidlmobley
mattwthompson
sncr0
Hi Folks,
Is your feature request related to a problem? Please describe.
Feature/documentation request
We are running simulations of various SARS-CoV-2 proteins. There are certain simulations in which a covalent bond between a standard amino acid and an OpenFF parameterized ligand might be necessary. Examples include the spike protein glycosylations or covalent inhibitors.
Describe the solution you'd like
Parameterizing either a molecule that gets added onto an amino acid as a post translational modification or parameterizing the entire modified residue is clearly possible. However, in both cases, these molecules need to be covalently coupled to the standard amino acids. A simple example showing how to setup such a simulation with Amber would be very helpful.
These examples were particularly helpful: https://github.com/openforcefield/openforcefield/tree/master/examples/using_smirnoff_with_amber_protein_forcefield
Describe alternatives you've considered
I have considered parameterizing the entire post translationally modified residue, then converting it to a system, then serializing the system to XML, then attempting to manually reformat the ligand system's XML into Amber format protein XML file and saving it as amber14/protein_posttransmod.ff14SB.xml. This seemed rather error prone.
Another option that seems possible (and which might also benefit from a simple or easier to find example) could be plugging OpenFF into OpenMM's residue generator.
Another option could be LibraryChargeHandler?