[gmx-users] MD at different pH

[João Henriques]

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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