[gmx-users] MD at different pH

Thu May 4 15:12:34 CEST 2017

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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