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

Antonio Baptista baptista at itqb.unl.pt
Tue Feb 28 17:10:39 CET 2006

On Tue, 28 Feb 2006, Tsjerk Wassenaar wrote:

> 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 :)

Actually, two constant-pH MD studies of polylysine were recently done:
one by Hunenberger's group (J Phys Chem B 108:13551) and another one
by our group (J Phys Chem B 110:2927). So, it is true that it is
computationally demanding, but it is no longer prohibitive,
really. Our study is actually closely related to the issues raised by
Maxim, because our aim was to include ionic strength effects in a
constant-pH MD method that we developed before (J Chem Phys
117:4184). Our main methodology used Generalized Reaction Field
without ions (after a small hack in Gromacs allowing ionic strength to
be given as an external parameter). But we tested also a PME+ions
methodology that ensures both average electroneutrality and proper
ionic strength, and which gave results very similar to the GRF ones
(you can check our JPCB paper). Although the system was not extremely
well-behaved in terms of equilibration (both GRF and PME), we didn't
have problems as serious as those described by Maxim. The stochastic
protonation changes during constant-pH MD periodically "kick" the
protein, and this tends to produce higher fluctuations in all
properties (as it should in the correct semi-grand canonical ensemble)
and may perhaps help to achieve a better and/or faster sampling when
compared to "normal" MD. That may be the reason why our PME+ions
simulations do not get stuck in the helical state, unlike Maxim's
ones. There are some evidences that electrostatic periodicity (eg,
PME) may lead to artificial stabilization of folded structures (eg,
check some of the papers by Hunenberger's group), which may explain
the problems with the "normal" simulations.

Hope this helps,


> 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

Antonio M. Baptista
Instituto de Tecnologia Quimica e Biologica, Universidade Nova de Lisboa
Av. da Republica, EAN, ITQB II, Apartado 127
2781-901 Oeiras, Portugal
phone: +351-214469619         email: baptista at itqb.unl.pt
fax:   +351-214411277         WWW:   http://www.itqb.unl.pt/~baptista

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