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

From: Mohammad Salem <>
Date: Thu, 27 Aug 2015 16:44:10 -0600

Hi All,

I’m on the same project, so may be I would explain more:

We are using a green fluorescent protein whose chromophore is removed. The protein then has a barrel-shaped structure and there is a hollow space inside that can accommodate a molecule (chromophore). We then have an idea about the pose it should assume in the pocket. We want to see whether the molecule would like to get inserted into the interior of the barrel if we have the protein and the molecule freely in solution.

Does this sound reasonable to do with umbrella sampling in AMBER?

> On Aug 26, 2015, at 6:26 AM, David A Case <> wrote:
> 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
> complex.
> 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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