From: Giacomo Fiorin (giacomo.fiorin_at_gmail.com)
Date: Wed Aug 12 2020 - 13:20:17 CDT
This is not a trivial problem, so no need to apologize. The problem of
hidden barriers is ubiquitous in PMF calculations and there is no general
solution to fix it. What you suggest in terms of comparing upper and lower
leaflet PMFs is reasonable, but ultimately you will have to check if it
works, and understand why it may not.
One additional thing that I may suggest, as an alternative to using SMD to
initialize the windows, is trying to prepare the initial membrane structure
with the permeating molecule already embedded at the intended depth for
each window, and then equilibrate it. For a lipid bilayer with
exceptionally slow diffusivity I found this to give fairly accurate
permeabilities:
https://doi.org/10.1016/j.bpj.2020.01.044
compared to previous computations that used SMD to prepare the windows
before the equilibrium sampling. As for the sampling method, Ius
One important thing that you need to keep in mind for a peptide is that its
internal structure and orientation may be just as important, or even more
so than the Z-depth. So whatever you do, I would spend some time in
comparing different approaches of preparing a few specific initial
structures, rather than go directly for a PMF computation across the whole
bilayer. A set of well-equilibrated unbiased MD simulations is always more
informative than an unconverged PMF computation using a bad reaction
coordinate.
Giacomo
On Wed, Aug 12, 2020 at 1:46 PM Rukhsar Ali <arukhsar052_at_gmail.com> wrote:
> Thank you for your email.
>
> I know that the Z-distance projection is the most well-used RC to
> calculate permeation events and I get that ABF is not an out-of-equilibrium
> pulling experiment. Still, there may have hidden barriers related to
> peptide orientation, secondary structures, formation of pores etc. This
> article https://pubs.acs.org/doi/abs/10.1021/jp506633n suggests that
> hysteresis calculation is a good indicator for hidden barriers.
>
> In these articles (by Tse et al), convergence was assessed by the
> hysteresis between upper and lower leaflet profiles.So, this should be
> similar to running ABF windows by taking alternate end states as initial
> structures.
>
> Sorry for being naive
>
> On Wed, 12 Aug 2020, 10:03 pm Chris Chipot, <chipot_at_illinois.edu> wrote:
>
>> Ali,
>>
>> it is not quite clear what you refer to backward and forward PMF—ABF is
>> run at thermodynamic equilibrium; it is not an out-of-equilibrium pulling
>> experiment. There are many published applications out there, whereby the
>> free energy was measured, using ABF, in the direction normal to a lipid
>> bilayer. These free-energy calculations are usually prefaced by steered MD
>> and long equilibration stages to prep the different windows along the
>> permeation pathway. You may want to look at Tse et al. JCTC 2018, 2019.
>>
>> Cheers,
>>
>> Chris Chipot
>>
>>
>> On 8/12/20 6:13 PM, Rukhsar Ali wrote:
>>
>> Hi,
>> I'm very new to the ABF protocol to calculate PMF. I'm wondering, if I
>> want to calculate a backward PMF for a peptide insertion process into a
>> bilayer, should I just pick initial structures near the lower boundary end
>> state for each window and run the same simulations as in forward PMF
>> calculations? I mean, for a window 10A-12A (along 'distance Z' colvar), I
>> have taken the initial structure around 12A during forward PMF calculation.
>> So now, for the backward PMF, should I just take the initial structure near
>> 10A?
>>
>> Thanks.
>>
>>
>>
>> --
>>
>> Chris Chipot, Ph.D.
>> CNRS research director, University of Lorraine
>> Adjunct professor of physics, University of Illinois, Urbana-Champaign
>>
>> _______________________________________________________________________
>>
>> Chris Chipot, Ph.D.
>> Theoretical and Computational Biophysics Group
>> 3161 Beckman Institute for Advanced Science and Technology
>> University of Illinois at Urbana-Champaign
>> 405 North Mathews
>> Urbana, Illinois 61801 Phone: (217) 244-4361
>>
>> E-mail: chipot_at_illinois.edu
>> Christophe.Chipot_at_Univ-Lorraine.fr
>> Web: https://physics.illinois.edu
>> http://www.lia-uiuc.cnrs.fr
>>
>> The light shines in the darkness,
>> and the darkness has not overcome it
>> John 1:5
>> _______________________________________________________________________
>>
>>
-- Giacomo Fiorin Associate Professor of Research, Temple University, Philadelphia, PA Research collaborator, National Institutes of Health, Bethesda, MD http://goo.gl/Q3TBQU https://github.com/giacomofiorin
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