Free energy calculation of proton transfer with FEP

From: Huihui Liu (
Date: Sat Apr 27 2013 - 03:49:10 CDT

I would like to calculate the free energy of proton transfer between
Histidine and substrate in protein. The reaction could be described as
His + HA ---------> His(+) + A(-)
Could it be calculated with FEP? If yes, is it necessary to subtract a
reference value?

I have tried to simulate the process with FEP in the bulk, where His and HA
were loosely constrained 17 angstrom away from each other (cut off is 12
angstrom) so that they are independent. The free energy is about
-120kcal/mol, greatly different from the theoretical value calculated by
pKa with the formula deltaG=-RTln(K). Where am I wrong?

Thanks a lot,

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