AMBER Archive (2005)

Subject: Re: AMBER: DNA base-flipping: TI vs PMF

From: Peter Varnai (pv232_at_cam.ac.uk)
Date: Thu Jun 02 2005 - 12:21:56 CDT

Dear Lauren,

You are proposing an alchemical path to calculate the free energy of
base flipping. The problem is that you do not have distinct parameters
or topology to describe the flipped and closed states; charge
distribution or bonded interactions are presumed to be the same in the
two conformations and thus the direct interconversion is not possible
between these states.

You could take the flipped or the closed state as starting point and
make the flipping nucleotide disappear in both cases, but not the
opposite (water -> flipped in/out directions). However, the common
"water" state would contain quite an unphysically deformed piece of
DNA that would take a long time to relax.

If I understand the problem correctly, you are interested in the free
energy difference between the two end states, this is what the above
procedure can give you, at least in principle. But I am not sure why
you are then worried about the definition of the exact pathway between
these states. If you want to "see" the pathway, you need to use a
progress variable to project the free energy from some unrestrained
simulation (unlikely to see the event even once) or transition path
sampling procedures or simply use umbrella sampling along the progress
coordinate. A possibility could be to use the rms difference as the
coordinate (targeted MD) - that I have personally used successfully in
the past for this kind of problems.

Good luck,
Peter

On Tue, 31 May 2005, Lauren O'Neil wrote:

> I would like to calculate the free energy change for the process of
> base-flipping in DNA using Amber. I have been working with the online
> tutorial of thermodynamic integration in Amber and have a few questions as to
> how I could implement this for the base-flipping of damaged DNA.
> Along the lines of the tutorial I was thinking of a cycle in which DNA
> (flipped-in)-->water and DNA (flipped-out)--> water using dummy atoms. Can
> Amber handle using that many dummy atoms (DNA = duplex 16-mer)? How could I
> ensure that the two "water" states are the same, or can I? To get around the
> waters being the same I was also thinking of starting with a water box that
> contained both the flipped-in and flipped-out DNA (as dummy atoms) and then
> going both the flipped-in and flipped-out directions to get the free energy
> difference. The larger question is - How do you determine that the reference
> state (water) is the same for any cycle? Also, could this be done directly
> (without a common reference state)? If yes, can Amber do this?
> I am interested in using thermodynamic integration rather than potential of
> mean force for this calculation because of the choice of path for the flipping
> process. Any thoughts??
-----------------------------------------------------------------------
The AMBER Mail Reflector
To post, send mail to amber_at_scripps.edu
To unsubscribe, send "unsubscribe amber" to majordomo_at_scripps.edu