[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: Homeo Morphism <homeo.morphizm.gmail.com>
Date: Tue, 29 Oct 2019 17:10:49 +0300

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?

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Received on Tue Oct 29 2019 - 07:30:02 PDT
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