[gmx-users] MD at different pH

Smith, Micholas D. smithmd at ornl.gov
Thu May 4 14:44:24 CEST 2017

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:





(Ok So I was wrong, you can do it in gromacs, but you have to hack at the lamba-dynamics stuff)


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.


> 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

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