[gmx-users] Free Energy calculations of peptide-protein binding

[Daniel Seeliger]

Hi Ehud,

we recently developed an extended amber99sb forcefield + some scripts which 
probably can do exactly what you want (setting up alchemical mutations for any 
amino acid mutation except for proline).
We tested it by calculating thermostability differences for a set of 100+ 
mutations of an enzyme and got quite accurate agreement with experimental data 
(R=0.86 ).
If you want I can send you the stuff you need to set up the simulations. 
Details about simulation parameters you can find in the paper. 
( http://www.cell.com/biophysj/abstract/S0006-3495%2810%2900216-X  )

In general I would not use a plain thermodynamic integration scheme because it 
does not converge very well, especially for large mutations.
We used a Crooks-based non-equilibrium scheme which worked quite well but 
there are also other protocols around (multi-state BAR) which probably do 
equally well.

-Daniel

On Monday 05 July 2010 04:35:17 pm Ehud Schreiber wrote:
> Dear GROMACS users,
> 
> 
> 
> I am investigating a certain peptide which is well bound to some
> protein; their configuration is known from the PDB.
> 
> My aim is to compare the binding free energies of several variants of
> the peptide.
> 
> In particular, I wish to mutate some amino acids to others.
> 
> I have read some tutorials and mailing list messages; still, I have
> several questions unanswered.
> 
> 
> 
> I plan to use the Thermodynamic Integration (TI) method in an
> "alchemical" setting, in which I "turn off" the side chain.
> 
> The "naked" amino acid will then be my reference point comparing to real
> amino acids.
> 
> In this way I should be able to obtain, using the usual thermodynamical
> cycle, the binding free energy difference of two amino acids (Delta
> Delta G), which is sufficient for my needs and should be more accurate
> than computing absolute binding free energies (Delta G).
> 
> 
> 
> 1) Does this sound like the best approach?
> 
> 2) In particular, is it O.K. to use a "naked" amino acid (with no side
> chain at all) as the reference, or should Glycine or Alanine be used?
> 
> 3) Following the above procedure, I still would not achieve a "naked"
> amino acid.
> 
>      Rather, a side chain "ghost" remains, non-interacting but still
> bonded to itself and to the C-alpha.
>      Is it correct to assume that the contribution of such a "ghost"
> would cancel between the free and bound peptide?
> 
> 4) Are the OPLS-AA force field, theTIP-3P water model and the NpT
> ensemble good choices?
> 
> 
> 
> I have seen two methods used to make the change between the initial and
> final states.
> 
> The first (and simplest) is to use the couple-moltype parameter of
> mdrun.
> 
> However, this seems to change a whole molecule, while I'm interested in
> changing only a part (the side chain).
> 
> 
> 
> 5) Can I define the side chain and the amino acid backbone as different
> molecules, and change the former, still connecting them one to the
> other?
> 
> 
> 
> Alternatively, the topology of the B state can be explicitly provided
> (as described e.g. in section 5.7.4 of the version 4.0 user manual).
> 
> 
> 
> 6) The atom charges can be specified for state B, as appropriate for
> turning off the Coulomb interactions.
> 
>      In order to turn off the vdW ones, must I define new atom types?
> 
> 7) Are there perhaps such amino acid variants already built?
> 
> 
> 
> Finally, some technicalities:
> 
> 
> 
> 8) I have seen the sc-alpha parameter (when sc-power = 1) given the
> values 1.0, 0.7 and 0.5. What is recommended?
> 
> 9) Should I employ DispCorr = EnerPres ?
> 
> 
> 
> Thanks,
> 
> Ehud Schreiber.
> 

-- 
Dr. Daniel Seeliger
Computational Biomolecular Dynamics Group
Max-Planck-Institute for Biophysical Chemistry
Tel. +49 (0) 551-201-2310
http://wwwuser.gwdg.de/~dseelig