Re: [AMBER] What is the best way to study a dynamics route of a molecule to enter a protein

From: David A Case <>
Date: Wed, 26 Aug 2015 08:26:19 -0400

On Tue, Aug 25, 2015, Wenyu Qian wrote:
> I have a protein with an empty pocket. I want to calculate the free energy
> of insertion of a molecule from solution to that pocket. I have a sort of
> idea on the pathway it should take.
> I think I can do this with umbrella sampling, but I am not sure how to. I
> viewed the tutorial about umbrella sampling, but it was only about
> conformational change.

This depends on what you wish to compute. If you want the free energy
difference between the bound and unbound states, this is usually handled by
"alchemical" methods, where the ligand is annihilated in the ligand pocket,
and in free solution. More approximate "end-point" methods (usually more
appropriate for surveying large numbers of ligands) include MM-PBSA and
related methods, and various scoring scheme for docking. If you do not have
an experimental struture for the bound complex, you should certainly start
with docking programs (not with Amber) generate plusible poses for the

On the other hand, if you wish to estimate the free energy *profile* along
the binding path, umbrella sampling and its variants can be useful. This is
often a very difficult thing to carry out for a protein ligand complex, not
least because there are often (many) weakly-bound sites with the ligand near
the protein surface, that are difficult to sample adequately.

The trypsin-benzamidine complex has been studied an number of times in this
latter fashion. See, e.g. PNAS 112: E386-391, 2015, and references in there
to earlier work.

....good luck....dac

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Received on Wed Aug 26 2015 - 05:30:03 PDT
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