[gmx-users] MD at different pH

Thu May 4 16:23:22 CEST 2017

Thank you all for your valuable inputs.
Thanks and Regards,
Anu George

----- Original Message -----
From: "João Henriques" <joao.m.a.henriques at gmail.com>
To: gmx-users at gromacs.org
Sent: Thursday, May 4, 2017 7:00:14 PM
Subject: Re: [gmx-users] MD at different pH

I didn't mean to imply that you were excluding them, I merely wanted to
complement your list :) Still, I'm sure we're missing a couple other names
as well. It just goes to show that multiple flavours of constant-pH MD
methods do exist, implemented with several different MD packages.
Unfortunately not all of them are available straight out of the box and may
require further modifications to force fields as well.

/J

On Thu, May 4, 2017 at 3:20 PM, Smith, Micholas D. <smithmd at ornl.gov> wrote:

> Thank you for pointing out António Baptista and Miguel Machuqueiro's
> groups. I hadn't intended to exclude them
>
> ===================
> Micholas Dean Smith, PhD.
> Post-doctoral Research Associate
> University of Tennessee/Oak Ridge National Laboratory
> Center for Molecular Biophysics
>
> ________________________________________
> From: gromacs.org_gmx-users-bounces at maillist.sys.kth.se <
> gromacs.org_gmx-users-bounces at maillist.sys.kth.se> on behalf of João
> Henriques <joao.m.a.henriques at gmail.com>
> Sent: Thursday, May 04, 2017 9:12 AM
> To: gmx-users at gromacs.org
> Subject: Re: [gmx-users] MD at different pH
>
> P.S.: By "fully integrated" I meant that their modifications to Gromacs
> were never submitted/added to the main public distribution. Their method is
> obviously integrated with Gromacs, otherwise it wouldn't run, so it was a
> poor choice of words. Plus it requires third-party software for the
> Poisson-Boltzmann/Monte Carlo steps.
>
> On Thu, May 4, 2017 at 3:02 PM, João Henriques <
> joao.m.a.henriques at gmail.com
> > wrote:
>
> > Technically, Helmut Grubmüller's group is not the only performing
> > constant-pH MD using Gromacs. António Baptista and Miguel Machuqueiro's
> > groups in Portugal have done it with explicit solvent since 2002:
> >
> > http://aip.scitation.org/doi/abs/10.1063/1.1497164
> >
> > It is not fully integrated in Gromacs, making it difficult to use for
> > someone outside the group, but I thought their names had to be mentioned
> > given their extensive contribution to this field since its early days.
> >
> > /J
> >
> > On Thu, May 4, 2017 at 2:44 PM, Smith, Micholas D. <smithmd at ornl.gov>
> > wrote:
> >
> >> Although this is the gromacs mailing list, it should be mentioned that
> >> "constant" pH simulations do exist...you just have to use a different MD
> >> simulation packages (such as Amber or CHARMM) to allow protonation
> states
> >> to change on the fly. See the following:
> >>
> >> http://pubs.acs.org/doi/abs/10.1021/ct2006314
> >>
> >> https://link.springer.com/article/10.1007/s00894-012-1680-0
> >>
> >> https://www.nature.com/articles/srep22523
> >>
> >> https://www.ncbi.nlm.nih.gov/pubmed/16878971?dopt=Abstract&holding=npg
> >>
> >> https://www.ncbi.nlm.nih.gov/pubmed/21687785?dopt=Abstract&holding=npg
> >> (Ok So I was wrong, you can do it in gromacs, but you have to hack at
> the
> >> lamba-dynamics stuff)
> >>
> >>
> >> https://www.ncbi.nlm.nih.gov/pubmed/22694266?dopt=Abstract&holding=npg
> >>
> >>
> >> In general; however, Justin is right. It is much easier, and efficient
> to
> >> just assign the protonation states at the onset and keep them fixed so
> that
> >> you have a "fixed-pH"; however, if the sites are known to transistion
> from
> >> protontated to deprotonated frequently in your solvent, than a  CpHMD
> >> simulation can be used.
> >>
> >> Good Luck!
> >>
> >> ===================
> >> Micholas Dean Smith, PhD.
> >> Post-doctoral Research Associate
> >> University of Tennessee/Oak Ridge National Laboratory
> >> Center for Molecular Biophysics
> >>
> >> ________________________________________
> >> From: gromacs.org_gmx-users-bounces at maillist.sys.kth.se <
> >> gromacs.org_gmx-users-bounces at maillist.sys.kth.se> on behalf of Justin
> >> Lemkul <jalemkul at vt.edu>
> >> Sent: Thursday, May 04, 2017 8:29 AM
> >> To: gmx-users at gromacs.org
> >> Subject: Re: [gmx-users] MD at different pH
> >>
> >> On 5/4/17 1:02 AM, Anu George wrote:
> >> > Through the simulation, I am trying to find out if the binding free
> >> energy of the drug-protein complex is strong enough for the drug to be a
> >> good inhibitor of the protein.
> >> > so, does the pH of the simulation matter as in reality the active
> >> monomer exists in acidic pH conditions?
> >>
> >> You have to model whatever the realistic conditions are, whether that's
> >> in vivo
> >> or in vitro.  This is part of good experimental design.  If your target
> >> exists
> >> in a mildly acidic microenvironment, that's what you should model.
> >> Binding
> >> thermodynamics do depend on protonation states (in some cases, quite
> >> strongly)
> >> so if you model one state and try to relate it to data that exist in
> >> another,
> >> you're comparing apples to oranges and you've wasted a lot of time and
> >> resources.
> >>
> >> Also, dispel with the notion of "pH of the simulation" because such a
> >> thing does
> >> not exist.  You'll be modeling a constant protonation state and there
> are
> >> no
> >> dissociable protons floating around.  You're going to do a simulation
> >> using the
> >> dominant protonation state of a given set of molecules at a
> corresponding
> >> experimental pH.
> >>
> >> -Justin
> >>
> >> > Thanks
> >> > Anu George
> >> >
> >> > ----- Original Message -----
> >> > From: "Justin Lemkul" <jalemkul at vt.edu>
> >> > To: gmx-users at gromacs.org
> >> > Sent: Wednesday, May 3, 2017 8:15:33 PM
> >> > Subject: Re: [gmx-users] MD at different pH
> >> >
> >> >
> >> >
> >> > On 5/3/17 10:04 AM, Anu George wrote:
> >> >> Thanks Justin for the information.
> >> >> But I had a further question regarding the simulation-if the active
> >> monomer exists only in the acidic pH, then will carrying out a
> simulation
> >> of the monomer with a drug  at neutral pH help?
> >> >
> >> > That depends on what your scientific goals/questions are and what you
> >> are
> >> > actually trying to model.
> >> >
> >> > -Justin
> >> >
> >> >> regards,
> >> >> Anu George
> >> >>
> >> >> ----- Original Message -----
> >> >> From: "Justin Lemkul" <jalemkul at vt.edu>
> >> >> To: gmx-users at gromacs.org
> >> >> Sent: Wednesday, May 3, 2017 5:37:33 PM
> >> >> Subject: Re: [gmx-users] MD at different pH
> >> >>
> >> >>
> >> >>
> >> >> On 5/2/17 11:31 PM, Anu George wrote:
> >> >>> Dear Gromacs users,
> >> >>> I am working on a tetramer(human beta-2 tryptase) protein which
> exist
> >> as an active monomer at an acidic pH of about 6..If I have to do a
> >> molecular dynamic simulation of the monomer with a small molecule,
> should
> >> the simulation be carried out  at this pH ? what are the steps I should
> >> follow?
> >> >>
> >> >> Calculate the pKa values for titratable residues and select their
> >> dominant
> >> >> protonation states at that pH when running pdb2gmx.
> >> >>
> >> >> -Justin
> >> >>
> >> >
> >>
> >> --
> >> ==================================================
> >>
> >> Justin A. Lemkul, Ph.D.
> >> Ruth L. Kirschstein NRSA Postdoctoral Fellow
> >>
> >> Department of Pharmaceutical Sciences
> >> School of Pharmacy
> >> Health Sciences Facility II, Room 629
> >> University of Maryland, Baltimore
> >> 20 Penn St.
> >> Baltimore, MD 21201
> >>
> >> jalemkul at outerbanks.umaryland.edu | (410) 706-7441
> >> http://mackerell.umaryland.edu/~jalemkul
> >>
> >> ==================================================
> >> --
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