Re: [AMBER] {SPAM?} Re: Suspicious pKas from CpHMD

From: Matthew Guberman-Pfeffer via AMBER <amber.ambermd.org>
Date: Thu, 9 Feb 2023 16:17:17 +0000

Hi Adrian,

Iím using the forcefield defined in leaprc.constph with TIP3P. Unless Iím 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>
Date: Thursday, February 9, 2023 at 11:08 AM
To: amber.ambermd.org <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 youíd 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>
> Date: Thursday, February 9, 2023 at 12:58 AM
> To: amber.ambermd.org <amber.ambermd.org>, Matthew Guberman-Pfeffer <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,
>
> VinŪcius Wilian D. Cruzeiro, PhD
> Postdoctoral Researcher
> Department of Chemistry
> Stanford University
> Twitter: .vwcruzeiro
> ________________________________
> From: Matthew Guberman-Pfeffer via AMBER <amber.ambermd.org>
> Sent: Wednesday, February 8, 2023 9:08 PM
> To: amber.ambermd.org <amber.ambermd.org>
> Subject: [AMBER] Suspicious pKas from CpHMD
>
> Dear AMBER Community,
>
> Iím 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
352-392-6972
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Received on Thu Feb 09 2023 - 08:30:08 PST
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