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

[Maxim Fedorov]

Dear Mark, 
> 
> > 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 experimentators have some unpublished data and there several 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.
But in this case I would have non-zero net charge of the box - 
how can I use PME then?
 
> 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.
Indeed. My general impression now is that SPC + PME is not a good 
combination 
for this task. The SPC water is too rigid and as was shown by 
Dzubiella and Hansen in 
a couple of theirs recent papers it tends to form some ice-like 
structures around charges.
The PME itself can also produce some overstabilisation - see Roberto 
D. Lins and Ursula Röthlisberger J. Chem. Theory Comput.; 2006 (many 
thanks to an unknown friend who forwarded my question to Roberto!).
So, I guess, I should play a bit with different water models. I am a 
bit afraid to change the PME by cut-off though. This poly-L-lysine 
business is only part of 
our tasks and for other systems the PME works better than cut-off. 



> > 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?
~1-2 ns.

Thank you for this interesting discussion,

Regards,

Maxim.

> 
> Mark
> 
> 
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