[gmx-users] binding free energy

[Alexander Alexander]

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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