Re: Question on restraint behavior when part of system decouples

From: Jérôme Hénin (jerome.henin_at_ibpc.fr)
Date: Mon Jan 29 2018 - 13:52:07 CST

>
>
> The protocol I have in mind is the one shown in the NAMD free energy
> tutorial, “Protein:ligand standard binding free energies…”, especially Fig.
> 1 and associated narrative (Paragraphs numbered 1-5, copied below). The
> idea is that only the conformation of the ligand is ‘pinned’ in the bulk
> simulation, while in the complex, ligand position, orientation AND
> conformation are restrained. I would think that the three types of
> constraint ‘capture’ three important components of small molecule binding
> in terms of entropy loss, and don’t understand why only one of these
> contributions is ‘picked out’ in the bulk simulation.

Because that's the only one that will make a difference. Translation and
rotation are just symmetry operations in the isotropic bulk.

Put simply, why not just annihilate the ligand in solution with no
> constraints?
>

That would be an option: but then you'd have to release the conformation
restraints in vacuum to get the free energy contributions. One reason to
avoid this is, if you have a flexible ligand like a peptide, the decoupling
calculation in bulk will converge faster under restraints. Then the
assumption is that the favored conformations in solution are not too
different than those in the binding site, so releasing the restraints there
is not too drastic.

And by the way, the tutorial implies that the purpose of the restraints is
> to avoid the ‘wandering ligand’ problem, where as the ligand decouples it
> starts moving around and gets tangled up with the protein, leading to huge
> energies and poor accuracy, a very real problem! - but I don’t see where
> it discusses entropy?

Well, not explicitly perhaps. It's included implicitly if the restraint
free energy calculations.

Best,
Jerome

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