Adrian,
So, the remedy is not simply to run separate CpHMD at very low and very high pH? Will that do any good? Or is REMD my only hope?
Best,
Matthew
From: Adrian Roitberg <roitberg.ufl.edu>
Date: Thursday, February 9, 2023 at 3:15 PM
To: Matthew Guberman-Pfeffer <matthew.guberman-pfeffer.uconn.edu>, AMBER Mailing List <amber.ambermd.org>
Subject: Re: {SPAM?} Re: [AMBER] Suspicious pKas from CpHMD
*Message sent from a system outside of UConn.*
ok, that is fine, you are using the correct combo.
So, indeed, what is happening is that you are not sampling protonation states well. I am guessing you have seens maybe one or two titrating events in your whole set of MDs.
If you are doing replica exchange in pH space, just add maybe one replica at pH 0 or 1, and one at 14 or more, to guarantee you will see some titration events.
If you are NOT doing remd, , then there is not much you can do. If the ASP and the LYS are interacting strongly, it would be hard to disentangle them except at very low or very high pH.
adrian
On 2/9/23 11:17 AM, Matthew Guberman-Pfeffer wrote:
[External Email]
Hi Adrian,
I’m using the forcefield defined in leaprc.constph with TIP3P. Unless I’m mistaken, the underlying forcefield is ff10, which is equivalent to ff99SB for proteins. Is there a different FF/solvent model that is recommended for CpHMD?
Best,
Matthew
From: Adrian Roitberg via AMBER <amber.ambermd.org><mailto:amber.ambermd.org>
Date: Thursday, February 9, 2023 at 11:08 AM
To: amber.ambermd.org<mailto:amber.ambermd.org> <amber.ambermd.org><mailto:amber.ambermd.org>
Subject: {SPAM?} Re: [AMBER] Suspicious pKas from CpHMD
*Message sent from a system outside of UConn.*
Hi Matthew
One more possible issue:
What exact force field and solvent are you using for your MD ?
the const pH method in amber (discrete model) is parametrized for a
given FF/Solvent pair. We have plans to update this, but it is not in
the release yet.
adrian
On 2/9/23 1:36 AM, Matthew Guberman-Pfeffer via AMBER wrote:
> [External Email]
>
> Hi Vinicius,
>
> Thanks for your quick reply. Your suggestion was very informative! The output showed me that the protonated fraction for Lys-8 and AS4-114 is always >0.99 and <0.005, respectively. So, the pKas are strange because only extremely rare transitions are being sampled.
>
> What are the lowest and highest extremes in pH you’d recommend testing? Is it 2 to 12 (the pKas range, I think can be measured in aqueous solutions)?
>
> Best,
> Matthew
>
>
>
>
> From: Vinicius Wilian Cruzeiro <vwcruz.stanford.edu><mailto:vwcruz.stanford.edu>
> Date: Thursday, February 9, 2023 at 12:58 AM
> To: amber.ambermd.org<mailto:amber.ambermd.org> <amber.ambermd.org><mailto:amber.ambermd.org>, Matthew Guberman-Pfeffer <matthew.guberman-pfeffer.uconn.edu><mailto:matthew.guberman-pfeffer.uconn.edu>
> Subject: Re: Suspicious pKas from CpHMD
> *Message sent from a system outside of UConn.*
>
> Hello Matthew,
>
> You should take a look at the fractions of protonated species as a function of pH for these residues. This will give you an idea on why you are getting these fitted values.
>
> One possibility is that you are having a conformational change and then your fractions of protonated species vs pH will not have a nice sigmoidal shape, what could explain the fitted values you got.
>
> Also, I would not exclude the possibility that you need to add more pH values, as you pointed out. Notice that the plots I am suggesting will tell you if this is what you need to do.
>
> I hope this helps,
>
> Vinícius Wilian D. Cruzeiro, PhD
> Postdoctoral Researcher
> Department of Chemistry
> Stanford University
> Twitter: .vwcruzeiro
> ________________________________
> From: Matthew Guberman-Pfeffer via AMBER <amber.ambermd.org><mailto:amber.ambermd.org>
> Sent: Wednesday, February 8, 2023 9:08 PM
> To: amber.ambermd.org<mailto:amber.ambermd.org> <amber.ambermd.org><mailto:amber.ambermd.org>
> Subject: [AMBER] Suspicious pKas from CpHMD
>
> Dear AMBER Community,
>
> I’m getting some really strange pKas for CpHMD simulations performed at pHs from 5 to 10. For example,
>
> LYS 8: pKa = 564.07106 (+- 9292.89711 ) ; Hill coefficient = 0.004 (+- 0.060 )
> AS4 114: pKa = -52.65171 (+- 144.03991 ) ; Hill coefficient = 0.046 (+- 0.112 )
>
> Each simulation was propagated for 40 ns. My CpH-relevant settings were icnstph=2, ntcnstph=100, ntrelax=100, and solvph = 5, 6, 7, 8, 9, or 10.
>
> Is there anything besides running the simulations for longer that I should try? Should I expand the range of considered pHs? What else can I try to get more reasonable pKas for these residues? Or, what should I inspect to see if something is going wrong?
>
> Best,
> Matthew
>
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Dr. Adrian E. Roitberg
V.T. and Louise Jackson Professor in Chemistry
Department of Chemistry
University of Florida
roitberg.ufl.edu<mailto:roitberg.ufl.edu>
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Dr. Adrian E. Roitberg
V.T. and Louise Jackson Professor in Chemistry
Department of Chemistry
University of Florida
roitberg.ufl.edu<mailto:roitberg.ufl.edu>
352-392-6972
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Received on Thu Feb 09 2023 - 12:30:03 PST
