FEP question

From: Matthew WIlce (matthew.wilce_at_med.monash.edu.au)
Date: Thu Sep 06 2007 - 08:32:09 CDT

Dear NAMDers,
I have a couple of questions regarding FEP.

I am using FEP and mutating a Cytosine into a Thymine, ADE and GUA. I
have set up the dual topologies so that it is the purine or
pyrimidine that is mutating while the rest of residue in not
changing. I have noticed that at the beginning of the FEP run the
purine or pyrimidine that is starting to grow moves around too much
and sometimes the ring flips ~180 degrees. When the ring flips 180
degrees it prevents a sensible outcome from the FEP. This also occurs
for the Cytosine ring towards the end of the FEP. Once lambda has
become greater than about 0.01 and the growing ring starts to
interact with the rest of the molecules it behaves much better.

For a purine to purine mutation eg ADE to GUA I could of course
modify the dual topology so that the all of the common atoms are
maintained throughout the FEP, and the same goes for the pyrimidines.
But I cannot see how a work around when the rings are quite different
eg. pyrimidine vs purine.

Is there a way to sensibly restrain/constrain the movement of the
growing component of the FEP so that it cannot 'float' around until
lambda1 passes say 0.01, and also apply similar restraints to the
shrinking component when lambda 1 is greater then ~0.99.

Has anyone done this? What impact could this have on the free energies?

I have thought of writing a tcl script that constrains the atoms at
the beginning and end of the FEP depending on lambda ?? but I am not
sure how. I want the growing and shrinking rings of the purine or
pyrimidine to stay roughly in the same place relative to each other
until their interactions with the rest of the molecule may cause them
to move if necessary and not have them moving because they are not
interacting.

I have tried using the namd parameters as suggested in the most
recent FEP tutorial as well as varying them but I have not been able
to resolve this. Even using a very low number of steps in each FEP
window (as low as 1000) does not stop the ring from sometimes flipping.

Thanks in advance,
Matthew

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