Hi Mike,
> My question is what you think will happen if I approximate the reaction
> coordinate as the distance between the end of each chromophore, so that
> I can sample from large distance (open) to a small distance (closed).
> Since the reaction path followed may not be the real one, I will not be
> able to extract information about the activation energy or rate
> constants. All I want for the moment however is to find out which
> conformer is more stable. Will I be able to extract the change in energy
> between the open and closed forms simply by subtracting the values at
> the two local minima either side of the activation hill of the free
> energy profile along the reaction coordinate?
Umbrella sampling seems to be a good choice for this kind of problem. In
my opinion, taking the chromophore distance as a reaction coordinate is a
sensible choice. You will see from your simulations if the 'far apart' and
'close together' conformations that you impose are equal to the open and
closed forms you want to compare. Subtracting the energies of the minima
at either end of the simulation will only give you the energy difference
between the conformations, not the free energy difference. The later is
what you want and can be obtained from the umbrella sampling free energy
curve.
> Another idea I had was to compute the free energy of solvation for each
> conformer separately using thermodynamic integration. I could then
> calculate the difference in free energy between open and closed and see
> how it varied depending on the solvent.
This TI based approach is in principle valid, but it means comparing two
states by transforming them both into a quite distant reference state. In
terms of sampling and convergence, this makes the problem much harder than
it has to be. Also, in the almost decoupled state (high lambda), the
solvent will not prevent your molecule from doing open-close
transformations any longer, so distinguishing between solvation free
energies for the open and closed states might be tricky.
There is another approach that you might want to look into, namely
doing MM-PBSA calculations on the open and closed state. This method makes
a few additional approximations, especially a continuum solvent
representation for part of the thermodynamic cycle, but might be well
suited for your system.
My choice would be to try MM-PBSA first and maybe umbrella sampling if you
do not encounter large conformational barriers in the transformation. TI
would not be my first choice for this problem, but it would be interesting
to see if you can get such a big molecule to disappear smoothly and how
the results compare.
These are of course just my comments to your questions, others on the list
might have different opinions...
Kind Regards,
Thomas
Dr. Thomas Steinbrecher
The Scripps Research Institute
10550 N. Torrey Pines Rd.
San Diego CA 92037, USA
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Received on Sun Dec 16 2007 - 06:07:08 PST
