[gmx-users] The trouble with dihedral restraints: frozen peptide backbones

Mark Abraham mark.abraham at anu.edu.au
Mon Oct 18 04:30:03 CEST 2010

----- Original Message -----
From: ms <devicerandom at gmail.com>
Date: Monday, October 18, 2010 8:23
Subject: [gmx-users] The trouble with dihedral restraints: frozen peptide backbones
To: Discussion list for GROMACS users <gmx-users at gromacs.org>

> Hi,
> It's a bit long but bear with me if you can. I'm getting quite 
> mad with this. Thanks :)
> Now. I am using Gromacs (4.0.7 currently) to create a custom 
> coarse-grained, no-solvent MD peptide model -one that contains 
> the backbone but has only C-alphas, no side chains.
> To enforce chirality in such a toy, I thought that a simple 
> (naive?) but functional idea could be that of enforcing a not-
> too-hard and wide-bottomed dihedral restrain on the phi angle, 
> like that:
> [ dihedral_restraints ]
> ; ai   aj    ak    
> al  type  label  phi  dphi  kfac  power
> ; phi C'(n-1) - N - CA - C'
>   3     
> 5       7       8       1        1      -90     75    2      1

Try mdrun -debug on a short run. What does it have to say about the parameter values for this dihedral restraint? Likewise gmxdump -s on the .tpr (though you will have to search around for F_DIHRES among other things, probably).


> so that the system is free to move in a large phi-angle space 
> without problems, but cannot go in the forbidden, symmetrical 
> glycine-like space. In testing, I set the force constant small 
> (10) so that the chain, even if with some difficulty, should be 
> able to bend and move by spending some energy in the "forbidden" 
> zones, if needed to achieve structure, etc.
> Now, the point is that *when* it works, it works quite well. But 
> sometimes -with "sometimes" being from 0% to 90% of times, 
> depending on details of what I am simulating- it totally 
> doesn't. That is: sometimes, starting from an extended 
> structure, the chain simply freezes. It is not static: it 
> wiggles a bit here and there, but it stays mostly extended. 
> Energies plots (g_energy output xvg's) are on average flat: that 
> is, they show the right noise for all components, but no 
> structure: nothing happens, for as much as 50 ns.
> Sometimes instead it works, and then you see that everything 
> works alright; the peptide structures, potential energy goes 
> down and down, etc.etc.
> There are no differences in minimization energies etc. from a 
> simulation that freezes and one that works. Moving the restraint 
> center doesn't help much. I *know* it's the restraints because 
> if I keep everything the same but I lower the force constant or 
> remove restraints altogether, the freezing bug happens no more -
> but then I have little or no more chirality, of course. I have 
> the following further facts:
> - It tends to happen more often for longer chains: 10 or 20-
> residue long chains work often OK, but a 40-long chain is 
> difficult to get "right".
> - It *never* happens, to my knowledge, if I put more than 1 
> chain to cluster in the box.
> - The Ramachandran plot of the extended frozen thing is "right", 
> meaning that it populates a reasonable (mostly beta) angle 
> space. During trajectory angles move quite a bit but stay in the 
> right (top-left) zone of the plot.
> - "Good"-behaving simulation often start with a short "frozen" 
> stretch: then the dihedral restraint energy suddenly jumps to 
> some above noise positive value, to accomodate some bending I 
> guess, and all goes downhill from there.
> - In frozen simulations, there's almost no LJ energy: the chain 
> does not self-interact.
> All of this, added to the apparent "randomness" of the 
> pathology, makes me think that the chain simply is stuck in a 
> situation where it has a too high barrier to properly bend -a 
> barrier which is not a "soft" one as the harmonic potential of 
> the restrain would make me think. This would explain why putting 
> more peptides and letting them bind together avoids the problem: 
> the potential energy of binding compensates for the bending when 
> you have more than one thing; but sometimes a single chain 
> cannot find itself to interact with, because it should bend 
> correctly to do so.
> And then, I read on the Gromacs website *this*
> http://www.gromacs.org/Documentation/How-tos/Dihedral_Restraints
> " 2. The manual is a bit unclear about whether this type of 
> dihedral restraint is stable for use near 180 degrees. Chris 
> Neale has found that everything appears to behave normally and 
> as expected over the entire range of dihedral angles including 
> 180 degrees. However, one must avoid the situation in which the 
> actual dihedral is close to 180deg away from the restrained dihedral."
> And I know that somehow the potential is discontinuous and/or 
> anyway not intended to be well-behaved everywhere:
> http://www.mail-archive.com/gmx-users@gromacs.org/msg12353.html
> "> On Tue, Feb 26, 2008 at 11:37 AM, David Mobley <[EMAIL 
> PROTECTED]> wrote:
> > >  The other way of putting what Mark said is that phi is 
> only meaningful on some range (-pi to pi, or 0 to 2pi, depending 
> on how you define it)
> > >  and so what you require is that the potential be 
> harmonic for the
> > >  region in which phi is meaningful. You don't care what 
> happens outside that. Or, in this case, you handle the issue by 
> mapping phi values  outside the allowed range back into 
> that allowed range."
> (I don't get what does it mean to "map back" phi values, by the way).
> I am no MD expert, so maybe my hypothesis is totally off, but I 
> am reasonably sure that either I do not understand correctly how 
> dihedral restraints work, or I am suffering by the discontinuity 
> of the way the potential is implemented (Or both). I would like 
> to know:
> - How can I try to understand in full what is going on
> - If my diagnosis sounds right, how can I start to correct the 
> problem.- If the problem is my naive approach to chirality, any 
> suggestion is welcome.
> Thanks A LOT if you've been patient enough to read until here! 
> And thanks even *more* if you can help!
> Yours truly,
> Massimo
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