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

Ehud Schreiber schreib at compugen.co.il
Mon Jul 5 16:35:17 CEST 2010

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

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


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 ?



Ehud Schreiber.


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