AMBER Archive (2007)

Subject: AMBER: Explicit water in implicit enviornment?

From: Hayden Eastwood (s0237717_at_sms.ed.ac.uk)
Date: Sun Sep 09 2007 - 14:57:26 CDT

Dear AMBER users

I am calculating binding energies of 4 ligands with a target protein.
However, I wish to compare these binding energies with that of the
ligand-free form of the protein in which the binding pocket is known
experimentally to house 4 water molecules.

I have calculated the binding energy of each of the ligands using the
generalized born model (igb=2) from the crystal structure via an ordinary
minmization with sander. However, when considering the ligand-free form of
the protein, I have used explicit water (TIP3).

My questions is therefore:

Is it meaningful to obtain the energy of the explicit water in the binding
pocket when the system is immersed in a continuum solvent?

The reason I am doing this and not just examining an empty binding pocket in
an implicit environment is because I believe that hydrogen bonding plays a
major role in stabilising the pocket, and the GB model (as I understand it)
could never accurrately account for the specific hydrogen bonding framework.
Am I right in assuming that the source of the inaccuracy (in examning
explicit water in an implicit solvent) would arise largely from the GB model
attempting to compute the non-polar contribution of the solvation free
energy for each explicit water particle? I say this because my understanding
is that the the non-polar contribution is derived via a surface-area
weighted proportion of an empirically derived organic molecule (that does
not share such properties with a single water particle.)

Any ideas as to how best to model H-bonding in the pocket, whilst still
maintaining the energetics associated with immersion in bulk water?

Many thanks

Hayden Eastwood

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