Re: questions regarding ABF sampling in a DMPC bilayer

From: Giacomo Fiorin (giacomo.fiorin_at_gmail.com)
Date: Wed Jan 18 2012 - 12:05:02 CST

Hello Ajasja:

1) Every molecular movement is slower in a lipid bilayer than in water,
because the lipid molecules are much slower to move than water molecules
(ns vs. ps).
2) Related to (1) and you yourself came up with a reasonable explanation.
3) If you lower the temperature, the motions of the lipids become even
slower because there is less kinetic energy available to overcome the
barriers, and you can't count on converged sampling any more. So most
likely, the simulation is not converged. If it were converged, any free
energy differences will depend on the specific system and maybe the force
field, but not the method you used to compute the free energy.
4) There is no special trick, samples in overlapping bins from different
calculations are summed together like you said. If the bin width of the
new and complete grid is different, that should be because you set a
different "width".
5) It is possible but you need to make sure that in the local minima of
your PMF the system is not in configurations that are altered by AMD. But
because you have so many lipid molecules, that is tricky to check. The
MacCammon paper describes how to modify the free energy reconstruction
method to factor in the AMD corrections.

Bests
Giacomo

On Wed, Jan 18, 2012 at 9:12 AM, Ajasja Ljubetič
<ajasja.ljubetic_at_gmail.com>wrote:

> Dear all,
>
> For the past half-year I had a lot of fun building a GPU cluster and
> running some ABF MD simulations in a DMPC bilayer. The system simulated
> is a spin-labelled peptide composed of alanine either in water or in a
> DMPC membrane (Fig1<http://lbf.ijs.si/ajasja/mails/ABF/enhancing-abf-DMPC/Fig1.GIF>
> ). The colvars (theta and phi) are the polar angles from the C-beta to
> the center of mass of the ring of the spin label. (Fig1<http://lbf.ijs.si/ajasja/mails/ABF/enhancing-abf-DMPC/Fig1.GIF>
> ).
>
> And in that time I have gathered quite a few ABF related questions:
>
> - *Why is the diffusion along the colvars so much slower in a DMPC
> bilayer than in water? *For example compare the colvar trajectories of
> Fig2 <http://lbf.ijs.si/ajasja/mails/ABF/enhancing-abf-DMPC/Fig2.GIF> (water)
> and Fig3<http://lbf.ijs.si/ajasja/mails/ABF/enhancing-abf-DMPC/Fig3.GIF>(DMPC). If the PMF along the colvars is approx flat, should it still matter
> that one system is in DMPC and another in water? So, is the slower
> diffusion an intrinsic property of the system or am I perhaps not setting
> some ABF parameters correctly?
> - *Why are there spikes in the forces applied by ABF in DMPC?* If one
> plots the applied forces in water and DMPC the patterns seems quite
> different. Larger forces are probably required to move lipid tails so
> perhaps this is normal. Fig3<http://lbf.ijs.si/ajasja/mails/ABF/enhancing-abf-DMPC/Fig3.GIF> (fa_theta
> and fa_phi)
> - *Why are there such small energy differences in PMF between water an
> DMPC? *(Fig4<http://lbf.ijs.si/ajasja/mails/ABF/enhancing-abf-DMPC/Fig4.GIF>).
> If the diffusion along the colvars is slower and more energy is needed to
> move lipids out of the way, then this should be seen in the PMF as higher
> energy barriers, right? But i'm seeing differences of only 2 kt, which does
> not seem that much. I thought this might be due to the fact that I'm
> running the simulations above the DMPC transition temperature. So I tried
> to lower the temperature (perhaps a bit too much), but at the lower
> temperature ABF fails to sample the phase-space very well (Fig5<http://lbf.ijs.si/ajasja/mails/ABF/enhancing-abf-DMPC/Fig5.GIF>
> ).
>
>
> - *How are gradients merged using InputPrefix?* From some quick plots (
> Fig6 <http://lbf.ijs.si/ajasja/mails/ABF/enhancing-abf-DMPC/Fig6.GIF>)
> the algorithm seems to adjust the offset (how?) and make the
> gradient continuous. Overlapping regions are probably averaged over and the
> counts of the overlap summed.
> - *Is it possible to use Accelerated MD with ABF (and get correct
> results)?* This is more of a brainstorming question. Using aMD I could
> "soften up" the lipid tails, but this seems very similar to increasing
> the temperature, which means I would not know at what temperature and what
> phase (liquid ordered, liquid disordered) the lipids are. If indeed this is
> even technically possible.
>
> Any insight is appreciated.
>
> Thank you and best regards,
> Ajasja Ljubetic,
> lbf.ijs.si
>

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