[gmx-users] Re: Counterions: influence on protein dynamics.

[Tsjerk Wassenaar]

Maxim,

I'd guess that you're polylysine doesn't come charged without having any
counterions in experiment. In the experiments, you're probably dealing with
hydroxide ions (and an additional amount of hydronium ions). I'd say these
will also influence the experimental findings. Therefore, there's more sense
in adding counterions, maybe even positive and negative, than there is in
creating a weird unphysical system.

Have you also considered that not all of your lysines need to be protonated
at pH=7? You'd actually want a constant-pH simulation with dynamic exchange
of proteins. But that's one bridge too far at present :)

Good luck,

Tsjerk

On 2/28/06, Mark Abraham <Mark.Abraham at anu.edu.au> wrote:
>
> Maxim Fedorov wrote:
>
> > Thank you for your message, but ...
> > It doesn't seem to answer for my particular question -
> > probably I should go in more details.
> > I am investigating the charge-driven unfolding of protonated polypetides
> > like poly-L-Lysine and other compbinations of
> > charged/neutral residials.
> > The  poly-L-Lysine with ambient conditions (pH~7) is protonated,
> > therefore, it is quickly unfolds from an initial helical structure
> > (which it has with pH >10) due to repelling of the side-chain positive
> > charges
> > I am intersting in the final conformation and unfolding dynamics of such
> > system.
> >
> > But ...
> > If I add some counterions into the box and allow them to approach
> > my polypeptide they screen the charges and it stabilises the initial
> > conformation. This effect of ion stabilisation is well known and it is
> > an intersting topic, but in this particular case I don't need this - I
> > want to unfold my structure as it happens in experiment (our
> > experimentators have some unpublished data and there several classical
> > papers of Sheraga and others about the pH driven unfolding of
> > poly-L-Lysine, which were published in 70ths).
>
> Charge separation is expensive energetically. Even though the unfolding
> may be charge-driven, it simply isn't going to be true that there are no
> counter-ions around in an experiment. Thus to have a realistic
> simulation you need to have some counter-ions (preferably at a realistic
> ionic strength)... but you say that "some counter-ions" stabilize the
> initial conformation. If you were adding charges to neutralize the
> system, you could try adding fewer counter-ions as a compromise.
>
> > So, I want to get rid of this screening effect by placing the ions
> > somethere far from the solute. But I would like to take it in some smart
> > way, to reduce some possible artefacts (see the points 1) and 2) in my
> > previous letter.
>
> Whatever you do to change the system is going to be a non-physical
> system. You say the physically realistic simulation doesn't follow
> experiment. Perhaps you should have a look at your simulation protocol,
> particularly the electrostatics treatment, to see if the fault might be
> there, rather than assume it's only the charge-screening effect. MM
> force fields are a model of reality, often applied in MD using further
> approximations to real physics, so there are multiple sources of problems.
>
> > The system seems to be well (say, more or less :-)) equilibrated - I
> > checked several geometrical and energetical properties they are fine.
> > And it doesn't want to unfold even for 50 ns - due to the charge
> > screening by ions. And it is not because the simulation time is still
> > too short - I made a good sampling of the phase space
> > with some Replica - Exchange run - in case of ions
> > the system has a global minumum in folded conformation.
> > In case of cut-off and absence of ions it doesn't have even local
> > minimum in the folded conformation - which correspond to the
> > experimental reslults and #common sense'.
> > If I don't use the ions and PME (simply using the cut-off) - the results
> > are more close to experiment - it quickly unfolds as it should be.
> > But I have to use the PME because for more comples systems the cut-off
> > doesn't suit our tasks.
>
> How long does the experimental system take to unfold?
>
> Mark
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--

Tsjerk A. Wassenaar, M.Sc.
Groningen Biomolecular Sciences and Biotechnology Institute (GBB)
Dept. of Biophysical Chemistry
University of Groningen
Nijenborgh 4
9747AG Groningen, The Netherlands
+31 50 363 4336
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