[AMBER] Is there any sense in even trying to model large conformational dynamics with molecular dynamics?

From: Homeo Morphism <homeo.morphizm.gmail.com>
Date: Mon, 20 Jan 2020 22:15:52 +0300

There's a certain protein. When a ligand binds to it, it experiences
massive confomational transition: its certain domain covers distance that
is on the order of several dozens of angstroms and for some individual
residues it's even more.

PDB structures for both ligand-free and ligand-bound (that is after this
massive conformational transformation has occurred) proteins are available.
There's also a set of experimentally verified mutations that make this
protein constitutively active.

I've been trying to model the conformational transition of this
constitutively active protein with molecular dynamics and I'm failing at

First, I tried to use so to say ordinary molecular dynamics - tip3p water,
NPT with Langevin thermostat, SHAKE enabled, 2 fs timesteps, etc. I got
nothing, but perhaps this is expected.

I then moved to accelerated MD, heating and cooling, just heating and
keeping it at high temperature, etc. Nothing. My accelerated MD attempts
are especially worthy of being mentioned: I was slowly raising boost with
each restart and the boost got so high that secondary structures began to
denature but there was no sign of the domain that is supposed to move even
beginning to move.

Has anyone tried something similar with AMBER?

Is my failure simply due to my not having found the right parameters and
modes of the simulation? There's still a replica exchange method that I
haven't tried yet. Self-guided langevin, etc.

Or are there some fundamental constraints that preclude these large
transitions from being modeled?

Any recommendations?

I use pmemd.cuda and it delivers 100-150 ns per day on our GPUs for the
protein in question, so it's not Anton 2, but we aren't slow either.

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Received on Mon Jan 20 2020 - 11:30:01 PST
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