[gmx-users] Gromacs Simulation Question

Justin Lemkul jalemkul at vt.edu
Sat Jan 7 21:12:46 CET 2017

On 1/6/17 5:14 PM, Academic Research wrote:
> Hello everyone,
> I have computationally designed several synthetic proteins that are not found in
> nature.
> My lab has limited resources for wet lab work and so I would like to use gromacs
> to simulate these proteins in water and see weather they unfold or aggregate. I
> know the best way is to actually express and purify these proteins and observe
> them, but my idea is to use molecular simulation to screen through these
> designed proteins and priorities the ones that appear not to unfold nor aggregate.
> 1. From your experiences, does my idea sound so crazy that I should abandon it?

It's an expensive venture, in terms of time and hardware requirements.  To study 
this adequately is going to require a lot of long simulations.  State of the art 
would probably be a couple microseconds total for each protein, more if you can 
get time on an Anton machine (where they routinely run for milliseconds).

The aggregation studies are even more expensive.  You'd have to start with 
multiple copies of the proteins in various states of unfolding, run replicates, 
and hope you can get some kind of converged sampling.  Having worked on small 
peptides (40-42 residues), this is not an easy task.  We did dimerization 
studies and a few hundred ns each was enough; for a larger protein I would think 
you'd need even more time.

Assuming you have adequate computational resources, I would guess this is 
probably at least a 1-2 year project.  I've invested similar time on small systems.

> 2. Does the Lysozyme in water tutorial from the Bevan Lab a good starting point?

My tutorial is a simple example of how to deal with any normal protein in water. 
  Using a cubic box is inefficient, especially if your systems are large, so 
don't do that.  Force field choice is also critical; don't just use OPLS because 
my tutorial does.  Look into what people are finding to be most accurate for 
IDPs and similar unfolding studies.

> 3. Are there existing tutorials or papers that simulate protein unfolding or
> aggregation that I could use as a starting point?

Your simulations are functionally no different from any protein-in-water system, 
so I doubt there's a tutorial for it.  The logic of my lysozyme tutorial holds, 
and then for larger systems it's just a matter of placing a couple copies of 
proteins in a box.  As for literature, yes, there are hundreds of papers 
published each year on protein unfolding and/or aggregation.  Consult the 
amyloid literature for numerous examples.



Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow

Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Facility II, Room 629
University of Maryland, Baltimore
20 Penn St.
Baltimore, MD 21201

jalemkul at outerbanks.umaryland.edu | (410) 706-7441


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