[gmx-users] binding free energy
Billy Williams-Noonan
billy.williams-noonan at monash.edu
Thu Jul 7 22:54:31 CEST 2016
Hi Justin,
The free ligand is the ligand in a box of solvent, and the complex is the
complex in a box of solvent. The complex would need to exist for the
duration of each of your lambda windows for this method to be reliable, and
the system would need to be in equilibrium as well... Have you considered
steered MD?
I would imagine that you will need pull code constraints holding your amino
acid in place as the VDW and coulomb lambdas get close to 1. However if
you are performing a relative FEP calculation, you can probably avoid using
restraints depending on whether State B still interacts with the ionic
surface.
You also may or may not find that you will need more coulomb lambdas
depending on how long each window is being simulated for.
You don't need a temperature lambda setting as you are not perturbing the
temperature, I don't think? Mass lambdas are unnecessary because you
should not be perturbing the mass either in an absolute FEP run. They are
still unnecessary in a relative run since the mass contributions should
cancel in a closed thermodynamic cycle. If you are perturbing dihedral
angles though, maybe consider using the FEP-lambdas setting.
Hope you've been going well! :)
Also, this would be my approach. I know absolute and relative FEP methods
work well for ligands binding to proteins, but I have no experience with
the exact situation that you're describing.
Good luck!
Billy
On 5 July 2016 at 19:09, Alexander Alexander <alexanderwien2k at gmail.com>
wrote:
> Hello Billy,
>
> Thanks for your response.
>
> Please confirm me that with bonded(complex), you mean the geometry of
> "amino acid+solidsurface+ water" that I should harvest in advance by normal
> MD simulation in which amino acid has been absorbed into the surface. and
> then this geometry should be used as the initial structure for each lambda
> in order to do FEP.
>
> Also, what do you mean please by the free (unbound)? If it is a geometry of
> again "amino acid+solidsurface+ water" in which amino acid has been
> solvated in water far away from the solid surface? or just an amino acid
> solvated in a box of water without solid surface (amino acid + water).
>
> Good to know that this strategy is the one mentioned in below paper (Figure
> 1):
> http://pubs.acs.org/doi/full/10.1021/ct400487e
>
> Here is the free energy parameter I am using in my calculation would you
> please comment on it, or let me know if I should consider any other
> parameter changes like mass-restrain-tempetatre-lambda?
>
> free-energy = yes
> init-lambda-state = MYLAMBDA ;;;from (i=0;i<15;i++)
> calc-lambda-neighbors = -1
> vdw-lambdas = 0.00 0.00 0.00 0.00 0.00 0.10 0.20 0.30 0.40
> 0.50 0.60 0.70 0.80 0.90 1.00
> coul-lambdas = 0.00 0.25 0.50 0.75 1.00 1.00 1.00 1.00 1.00
> 1.00 1.00 1.00 1.00 1.00 1.00
> couple-moltype = Protein_chain_A
> couple-lambda0 = vdw-q
> couple-lambda1 = none
> couple-intramol = no
> nstdhdl = 50
> sc-alpha = 0.5
> sc-coul = no
> sc-power = 1
> sc-sigma = 0.3
>
>
> Thanks.
> Regards,
> Alex
>
>
>
>
> On Tue, Jul 5, 2016 at 3:03 AM, Billy Williams-Noonan <
> billy.williams-noonan at monash.edu> wrote:
>
> > Just to clarify, the formula should be:
> >
> > dG (bind) = dG (complex) - dG (solv)
> >
> > Billy
> >
> > On Tuesday, 5 July 2016, Billy Williams-Noonan <
> > billy.williams-noonan at monash.edu> wrote:
> >
> > > You would want to perturb your amino acid in both the free (unbound)
> and
> > > complex (bound) aqueous states.
> > >
> > > Then if you subtract the free energy change from perturbing the free
> > > ligand, from that of perturbing the bound ligand, you should close the
> > > non-physical thermodynamic cycle and get a binding free energy.
> > >
> > > But you will need to make sure everything in your simulation is
> > > parameterised properly to get an accurate value. You will also need to
> > > make sure you have sufficient sampling time and lambda states.
> > >
> > > Good luck!
> > >
> > > Billy
> > >
> > > On Tuesday, 5 July 2016, Alexander Alexander <
> alexanderwien2k at gmail.com>
> > > wrote:
> > >
> > >> Dear gromacs user,
> > >>
> > >> I was wondering if anybody has any experience with binding free energy
> > >> calculation of a molecule (here amino acid) into a solid surface in
> > >> aqueous
> > >> solution using alchemical analysis?
> > >>
> > >> I have already tried successfully the tutorial of methane solvation
> free
> > >> energy in water and some other examples, but looks all of them are
> > >> solvation free energy and not binding free energy!
> > >>
> > >> Thanks.
> > >> Regards,
> > >> Alex
> > >> --
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