[gmx-users] Replacing a residue and continuing a simulation run

[Justin A. Lemkul]

J. Nathan Scott wrote:
> Hello all,
> 
> I was wondering, is it possible to replace a residue and then continue
> a simulation using the new parameters/geometry of the new residue? The
> reason I ask is that I am interested in performing simulations of
> proteins with tryptophan in its excited state following a lengthy
> equilibration with TRP in its ground state. I already have reliable
> excited state atomic charges for the TRP atoms, and I suppose that I
> will need to change at least some bonded terms to account for the
> altered geometry of the excited state.
> 
> I am still in the middle of reading the information that is out there
> regarding parameterizing new molecules (since I'm using the CHARMM FF,
> I've been starting to follow Alexander MacKerell's protocols), but I'm
> still not quite sure as to how one would practically do this residue
> replacement in the context of a Gromacs run. Will I need to manually
> edit my .top file, or is there perhaps another way to update the
> topology file with the new residue following the ground state
> equilibration? How about coordinates, will I need to transform the TRP
> coordinates to the excited state geometry by hand?
> 

You would have to hack the topology.  Coordinates are another matter.  If you 
start making ad hoc changes, then what's the point of a continuation? 
Presumably, if you've designed the residue's topology correctly (including both 
bonded and nonbonded parameters), then the residue will adopt the correct 
geometry on its own.

The complication comes with bonded interactions.  Are you using constraints?  If 
so, then changing bond lengths will cause the constraints to fail at step 0 (or 
very soon thereafter) and the simulation will crash.  You can get around this by 
setting "continuation = no" in the .mdp file, but again I wonder what the value 
of the continuation is.  You'd almost certainly have to forgo the use of .cpt 
files, supplying instead your .trr and .edr files to preserve as much of the 
previous ensemble as possible.  Even if you're not using constraints, the 
simulation may still fail if you're suddenly changing bond lengths, angles, etc 
by anything more than a very small amount.

> Perhaps the most important question: is there a better way to do the
> sort of residue replacement I'm contemplating, or is this something
> that is just inherently going to be a bit messy?
> 

I can't see any way around topology hacking.  If you need different parameters, 
you need a different topology.  It's going to be a bit messy, and I would 
encourage you to give some serious thought to the potential pitfalls I listed above.

-Justin

> Thanks very much for any insight or guidance you can offer!
> 

-- 
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Justin A. Lemkul
Ph.D. Candidate
ICTAS Doctoral Scholar
MILES-IGERT Trainee
Department of Biochemistry
Virginia Tech
Blacksburg, VA
jalemkul[at]vt.edu | (540) 231-9080
http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin

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