Tool for Repositioning disordered loop: TMD

From: Alexander Adams (
Date: Mon Jan 24 2022 - 11:01:36 CST

Dear community,

I have a protein built from a crystal structure, with a mostly disordered
loop that has been artificially generated. The loop is generated pointed in
the +x direction, and I'd like for it to point in the -x direction. To
achieve this, I used VMD to reposition the end residues to an approximate
location and saved these modified coordinates.

>From there I first tried running a minimization with the relocated end
residues held fixed to see if the rest of the loop would be relaxed to the
new orientation, but there were only small local arrangements, and the
artificially stretched bond between the altered end residues and the
original coordinates was unchanged.

Afterwards, I attempted to pull the end residues to the new coordinates via
TMD. I placed strong harmonic restraints on 2 alpha carbons in the main
body of the protein to keep the entire structure from simply translating,
and then set the alpha carbons of my end residues for TMD to the new
coordinates. When no progress was made over the course of 5 ns, I
iteratively increased TMDk to the point where there was constraint failure,
still without seeing an appreciable change in the coordinates. My TMD
settings are as follows:

TMD on
TMDk 2000
TMDOutputFreq 1000
TMDFile restraints/TMD_test.pdb
TMDLastStep 2500000

My questions: Is there a fundamental flaw in using these methods to achieve
my goal, or is it more likely that the error is in executing the TMD
simulation? If it's unsurprising that these procedures failed to produce
the desired effect, is there a different method I should use instead?

Thanks in advance for your time,
Alex Adams

University of Michigan, Ann Arbor
Ph.D. Candidate - Mayes Lab
College of Engineering - Chemical Engineering

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