Overestimated PMF

From: Felipe Merino (felipe.merino_at_mpi-muenster.mpg.de)
Date: Mon Jun 17 2013 - 09:43:07 CDT

Dear all,

I know this is a little bit off topic but i think somebody could help us
here. We have been doing some umbrella sampling simulations to calculate
the binding free energy of a protein-DNA complex. We are using the
minimal interatomic distance as reaction coordinate. The thing is that
the protein has two domains and we are only pulling them separately, so
in the end we have always an endpoint with the other domain still bound
(that was planned). In the end, the binding free energies are much
higher than expected (around 25 kcal/mol). The point is that it sounds
to me that there should be a correction on the PMF to account for the
"confinement" of being bound to the other (still attached) domain (very
much line in the case where you restrain the ligand when doing FEP
annihilation) but i am not sure if this is correct. Any insights for
this will be highly appreciated.

Best

Felipe

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