Re: [AMBER] if the ligand doesn't bind when it should, what does it say about quality of my simulations and what can I do?

From: Carlos Simmerling <>
Date: Tue, 29 Oct 2019 13:33:46 -0400

as you say, lots of things could be wrong. protonation states, temperature,
force field (protein, water and ligand), equilibration protocol, and so on.
You plan to lower temperature sounds good, and also critically evaluate
your equilibration, and ideally use a ligand model that has worked for
other people in the literature. also ensure it's not just an imaging

On Tue, Oct 29, 2019 at 10:11 AM Homeo Morphism <>

> I'm modelling CAMP binding to the CAMP-binding domain in one of the
> appropriate receptors. The relative coordinates of superficially bound CAMP
> are available from both the crystallographic structures and the results of
> docking in Autodock Vina -- they can be said to agree with each other.
> But when I start simulating the complex in Amber, CAMP molecule
> disassociates from the domain unnaturally quick and often. Even when it
> doesn't, I don't see in CAMP-binding domain even a glimpse of the
> conformational transformations that CAMP is described to cause --
> reorientation of side-chains, etc.
> To help with the disassociation problem, I've tried to disable SHAKE and
> for a while go to 1fs-timestep, hoping that once the pose is refined I
> could revert to 2 fs. 1 fs seems to help, but once I revert to 2 fs, it
> comes back.
> I've also tried increasing cutoff from the often-advised value of 9A to 13A
> -- doesn't seem to help.
> The rest of parameters are pretty standard. The periodic box is large
> enough. There's ions added for neutralization purposes. Etc. etc. etc.
> I realize that diagnosing this remotely is impossible, but perhaps there's
> a typical set of mistakes that people do in experiments like this...
> I've been also thinking of:
> 1) lowering the temperature from 310K to 300K;
> 2) increasing the viscosity/damping coefficient in the Langevin;
> 3) using NMR-restraints to force the ligand to hold on to the receptor.
> Does any of these sound plausible? And what else can be done?
> Thanks.
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Received on Tue Oct 29 2019 - 11:00:02 PDT
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