[gmx-users] SARS-CoV-2 main protease with ligand from acpype, but converting to vsites?

[Erik Marklund]

Hi Bjorn (and others interested in virtual sites for non-protein molecules),

We have an article in press where we describe our new tool Mkvsites, which is a great help when you want virtual sites for a new residue, ligand, etc. I will announce the article once it is available, but I might as well provide the tool already now: https://github.com/ErikMarklund/mkvsites

In short: Use topinspect.py to identify any atomtypes and interactions in your itp/top file that need to be added to the force field (not needed for some things, like nucleic acids already present in the force field, but for which no vsite parameters exist). topinspect.py optionally produces an rtp file, which is very helpful because it enables you to use pdb2gmx to place all dummy masses etc at a later stage. Then use Mkvsites.py to generate the required vsite parameters, including angle constraints for -OH groups. Put that in your force field, then prepare your system with pdb2gmx etc like you would for a vanilla protein system.

Look at the examples provided and get in touch if you need help. I am sure there are things we can do to improve the usability, so input is welcome. We have NOT automated the actual modification of force field files, since we have noticed that some of the input we have used for testing need human interpretation (e.g. to decide element type for new atom types). While we could implement some logic for that, it is difficult to foresee all possible flavours of input, and that strategy risk causing silent errors in the simulations.

Kind regards,
Erik
______________________________________________
Erik Marklund, PhD, Associate Professor of Biochemistry
Associate Senior Lecturer in Computational Biochemistry
Department of Chemistry – BMC, Uppsala University
+46 (0)18 471 4562
erik.marklund at kemi.uu.se<mailto:erik.marklund at kemi.uu.se>

On 27 Mar 2020, at 17:14, Bjorn Wesen <bjorn.wesen at gmail.com<mailto:bjorn.wesen at gmail.com>> wrote:

Hi list, I have a working sim of the solvated SARS-CoV-2 main protease
dimer from

https://www.rcsb.org/structure/6Y84

using amber99sb-ildn and pdb2gmx-generated vsites for speed, and wanted to
proceed by adding some of the various proposed inhibitor ligands to the sim
for further workflow testing, for example, this one:
"COCCOc1cc(C(=O)N=c2[nH][nH]c(C)c2-c2ccc(Cl)cc2)ccn1".

So I made a pdb of this and generated a .gro and .itp through one of the
online Acpype servers (the one at http://bio2byte.be/acpype ), but there is
no option to generate gmx vsites for getting rid of the hydrogen
bond-angles so I simply assume the result will blow up when running with
the longer timesteps the rest of the sim now uses.

I found a 5 year old post on this list with the same problem, with this
advice from Justin:
https://mailman-1.sys.kth.se/pipermail/gromacs.org_gmx-users/2015-October/101732.html


"At present, the simplest way forward is to take the information you have
in your
ligand topology from acpype and create an .rtp entry, then allow pdb2gmx to
process the whole thing and build the virtual sites on the ligand."

I was wondering, is this still the recommended method? I'm not
super-knowledgeable in the details of how to port something from the ITP to
the RTP formats. Should I just give up on doing it this way or is it an
"opportunity to learn the details" ;) Or is there a better way. Maybe some
other gmx tool to build the vsites for a ligand without having to go all
the way by creating the rtp stuff.

Also, yes, I could simply give up the vsites and run everything slower.
This is the fallback. Maybe some of these ligands simply won't work well
with these constructions at any rate.

Regards
/Bjorn
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