[AMBER] Trajectory determination and directionality in TI with softcore potentials

From: Ryan Muraglia <rmuraglia.gmail.com>
Date: Tue, 17 Sep 2013 15:39:22 -0400


I am using thermodynamic integration in AMBER 11 with softcore potentials,
and I am finding curious behavior that I cannot explain by reading the
manual or tutorials, so I was hoping that this would be an appropriate
place to seek an explanation or a suggestion for additional resources to

I have been trying to compute the free energy difference of the mutation of
an alanine residue (in an alanine tripeptide, AAA) to a valine residue
(making the tripeptide AVA) in a box of TIP3P water as a test case. I can
share my input files if they will help. The masked atoms are the sidechains
of the residues that are being swapped.

One of my sanity checks was to run the TI scheme "backwards," meaning that
in the groupfile, I flipped the order of the sander calls. I was expecting
that the dv/dlambda curves for the forward and backward processes would
mirror each other (with one taking on negative values). For example I would
expect that AAA -> AVA for lambda=0.25 would take on the negated value for
average dv/dl as AVA -> AAA for lambda=0.75, and that the values at
lambda=0.5 would be exact opposites.

I found that my expectation was not met. I used linear mixing of the
potentials (klambda=1) and I used the same, default, fixed random seed for
the Langevin dynamics (ig=71227) for each simulation, so I am not sure
where the deviation from my expected behavior is coming from. As I
understand it, 0.25 "forward" should be evolving according to the same
mixed potential as 0.75 "backward." Digging deeper, I found that the
trajectories of the two processes did not match, which could cause the
discrepancy in dv/dlambda values down the line.

All of this background is simply to ask, how are the trajectories
determined in TI? There is obviously something more nuanced than simply
stating that the system evolves according to a mixed potential. Do
non-masked atoms share the same trajectory in the two endpoint states (V0
and V1)? How is information from the two processes representing V0 and V1
combined to determine atomic positions in the next step? And most
importantly, is this discrepancy to be expected, and if so, can it be
characterized in a meaningful manner, or is it a byproduct of the

Thank you very much for reading. Any insight or suggestions for further
reading would be greatly appreciated.

Ryan Muraglia
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Received on Tue Sep 17 2013 - 13:00:02 PDT
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