Brian.
I mostly agree with you, but...
Suppose you know that there is a conformational change for a system, vs pH.
If you are unable to titrate them properly because they are "stuck", you
will never see that change.
So, in some cases, one needs to un-stick the residues by forcing
titration, etc.
Adrian
On 2/10/23 8:46 AM, brian.radak--- via AMBER wrote:
> [External Email]
>
> Just curious - but would it not be an acceptable result to simply say
> the pKa of ASP is < 5 and the pKa of LYS is >10? I don't know your
> particular endpoint here, but those predictions seem useful enough to
> me. We certainly make that exact declaration for other residues like
> tyrosine, serine, etc.
>
> What you really need to worry about is if the population stays near
> 100%, then drops to 0% and then spikes back up again -- that is almost
> definitely indicative of a sampling problem (as Vinicius suggested, it
> could mean a conformational change). REMD /could/ resolve that, but you
> might also need other forms of enhanced sampling.
>
> HTH,
>
> BKR
>
>
>
> On 2/9/23 3:19 PM, Matthew Guberman-Pfeffer via AMBER wrote:
>> 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
>>>
>>> _______________________________________________
>>> AMBER mailing list
>>> AMBER.ambermd.org<mailto:AMBER.ambermd.org>
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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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>>
>>
>> --
>>
>> 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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--
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 Fri Feb 10 2023 - 13:30:02 PST
