Hello again Rodrigo,
Just an addendum to my previous e-mail: AmberTools18 now has a tool that helps in finding reference energies for CpHMD automatically. It is called finddgref.py . You may find more information about it at the Amber 18 manual. You may use it to reproduce the values for the reference energies inside the cpinutil.py's library. The reference energies can also be obtained by performing TI calculations.
All the best,
Vinícius Wilian D. Cruzeiro
PhD Candidate
Department of Chemistry, Physical Chemistry Division
University of Florida, United States
Voice: +1(352)846-1633
________________________________
From: Cruzeiro,Vinicius Wilian D <vwcruzeiro.ufl.edu>
Sent: Thursday, February 21, 2019 8:41:16 PM
To: amber.ambermd.org
Subject: Re: [AMBER] Reference energies in CpHMD (constant pH MD) for HIP
Hello Rodrigo,
Interesting question.
In Amber, HID and HIE are "equally" deprotonated states. When the fraction of protonated species is computed in cphstats, it makes no distinction between the HID and HIE populations as they both count as "deprotonated" (even though you could easily extract the populations for HID and HIE yourself from the cpout file).
Now, explicitly addressing your question: when the reference energies for the HIP residue are computed, the usual approach is to first look at only the HID --> HIP transition and compute a reference energy associated only to this transition in such a way that the yielded pKa value in the simulation is 7.1. Then, the same procedure is repeated considering only the HID --> HIE transition but aiming at a pKa of 6.5. In the production simulations, we then consider all the 3 protonation states (HIP, HIE and HID) and use the two reference energies obtained previously. For completeness it is perhaps important to mention that the MC algorithm may attempt a protonation state change between the HIE and HID states (Note: as the target protonation states are chosen randomly, once you are at the HIE state the probability of attempting to go to either HID or HIP is 50%). When a protonation state change attempt between HIE and HID is performed, the reference energy associated with this transition is the difference between the two reference energies previously computed. You can check in details all the numbers used in Amber by executing: cpinutils.py --describe HIP .
Because all 3 protonation states are considered at the same time, at pH values 6.5 or 7.1 the fraction of protonated species is not going to be 50%. The effective pKa value is going to be between 6.5 and 7.1. This value depends also on the charge distributions across all 3 states.
I hope that helps,
And please let me know if you have any further questions,
Vinícius Wilian D. Cruzeiro
PhD Candidate
Department of Chemistry, Physical Chemistry Division
University of Florida, United States
Voice: +1(352)846-1633
________________________________
From: Rodrigo Pérez Cossio <rodrigoperez93.hotmail.com>
Sent: Thursday, February 21, 2019 7:16:48 PM
To: amber.ambermd.org
Subject: [AMBER] Reference energies in CpHMD (constant pH MD) for HIP
Hi!
I wonder if I understand it right.
Let's say we want to parametrize again HIP reference energies and test the new energies.
We have HIP, HID (pKa 6.5), and HIE (pKa 7.1).
If we run a CpHMD with the right reference energies, we should obtain:
1) At pH 6.5, the protonation fraction at D position is 50%. Then, the fractions should be: HIP+HID = HIE
2) At pH 7.1, the protonation fraction at E position is 50%. Then, the fractions should be: HIP+HIE = HID
Is this correct?
Thank you in advance!
Rodrigo Cossio Pérez
Universidad Nacional de Quilmes
Buenos Aires, Argentina
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Received on Thu Feb 21 2019 - 18:30:02 PST
