On Fri, Sep 11, 2015 at 9:02 PM, Rahul Ramesh <raramesh.umich.edu> wrote:
> Hi Jason
> I was successful in reproducing the CpHMD simulations for the HEWL protein
> and moved on to a non protein system. I chose the Succinic Acid system (
> COOHCH2CH2COOH) performed a Thermodynamic Integration. The delta G obtained
> was + 32 kcal/mol which was really strange as this compound has a pKa of
> 4.2. I abstracted a proton from only one of the COOH groups. When I used
> this value for CpHMD in AMBER , I got a 50% protonation at pH = pKa. I know
> the del G is totally off as this is a acid and it would like to dissociate
> as a result giving a negative del G. I checked the pKa and del G values of
> Aspartic and Glutamic Acid . Aspartic Acid has a pKa of 4 and a del G value
> of -26 kcal/mol and Glutamic Acid has a pKa of 4.4 and del G value of -8
> kcal/mol (data obtained from residues.py). I expected the del G value of
> Succinic acid to be in between these two values.
> Do you have an idea about why a positive value of del G is obtained in this
> case and CpHMD working fine for a wrong value of del G
>
Your mistake here is to attach any physical significance at all to the
value of the reference energy. The reference energy has *no* meaning,
whatsoever. There is a particular free energy value that is associated
with changing the charges of a residue from one set of charges to another.
Most force fields (with perhaps the sole exception being reaxFF) are not
parametrized to model chemistries (i.e., bond breaking and forming), and so
cannot be relied upon to get them even qualitatively correct.
This is the entire reason a "reference" energy is used in the first place.
The force field is known to get the free energy of protonation state
changes wrong -- it neglects desolvation of a proton and the effect of
nonbonded exclusions complicates the matter so much that it's difficult to
predict not only the magnitude of a reference free energy, but even the
sign that it will take.
The reason that CpHMD works in the first place is that these effects on the
free energy of deprotonation depend exclusively on the local environment
around the protonation site. So the reference energy is really a
correction factor that adjusts for the force field's inability to model
deprotonation correctly. Through the use of a thermodynamic cycle, it
reduces an intractable problem (i.e., determining the full
deprotonation/protonation free energy for each change) into a tractable
problem (i.e., determining the free energy of protonation/deprotonation in
a protein to the *same* deprotonation/protonation of a model compound whose
experimental pKas are known).
HTH,
Jason
--
Jason M. Swails
BioMaPS,
Rutgers University
Postdoctoral Researcher
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Received on Sat Sep 12 2015 - 20:00:03 PDT
