On Fri, Oct 15, 2010 at 1:15 PM, Lars Skjærven
<lars.skjarven.biomed.uib.no>wrote:
> Hi, and thanks for tips!
> The calculations are performed without the entropy contributions yes. The
> point was however to get a hint wether ligand binding to each of the two
> proteins strengthens or weakens the protein-protein interaction. Thus, the
> numbers in it self are not that interesting. I was more hoping that the
> relative change could be interpreted to aid in this question.
>
> It seems like an infinite cut-off value is common in MMPBSA calculations.
> I'm doing this on a protein ~3000 residues. Thus the GB calculations with
> infinite cut off are quite heavy. Would I be in trouble if I reduced the
> cut-off, to around 12Å?
>
Electrostatic energies scale as 1/r, as opposed to van der waals which scale
as 1/r^6 (a much much quicker rate of dying off). For periodic simulations,
the cutoff only affects VDW energies, as PME is used to calculate the
long-range EEL effects, so a small cutoff like 8Å is sufficient. However,
for implicit solvent, the cutoff also applies to EEL energies, so more care
has to be applied here. Note that the harmonic series does not converge, so
that should indicate that the effects of long-range EEL energies could be
quite significant if the cutoff is small enough to leave a large number of
pairs omitted.
Hope this helps,
Jason
> Kind regards,
> Lars Skjaerven
>
>
> On Thu, Oct 14, 2010 at 3:06 PM, case <case.biomaps.rutgers.edu> wrote:
>
> > On Thu, Oct 14, 2010, Lars Skjærven wrote:
> >
> > > I'm attempting to measure the binding free-energy of a protein-protein
> > > complex. Ligand binding to each of the two protein subunits are assumed
> > to
> > > weaken the binding energy between them.
> > >
> > > Thus, I performed 6 MD simulations of the complex with the two ligands,
> > and
> > > 6 MD simulations without the ligands. All simulations are 50 ns long.
> > MMPBSA
> > > was then used on each of the simulations to measure the binding free
> > energy
> > > in the two cases. 500 frames from each of the simulations were used in
> > the
> > > MMPBSA calculation.
> >
> > All your results seem quite reasonable. What is called "protein" and
> > "ligand"
> > is arbitrary, and your identification seems fine. It's also very good to
> > run
> > multiple simulations. What you are seeing looks to me like "natural"
> > fluctuations in estimates of protein-protein binding energies, although
> the
> > values are all very negative....are you leaving out the entropy
> > contributions?
> >
> > The "case 2" numbers do have bigger fluctuations: you could look for
> > structural differences in the individual simulations that might explain
> > some
> > of this. A good thing to do would be to pool all the snapshots (say for
> > "case
> > 2"), then cluster them. If important clusters have structures from each
> of
> > the six simulations, that would be good. If not, you would have evidence
> > that
> > individual simulations were getting trapped in some region of
> configuration
> > space.
> >
> > Using MMPBSA for protein-protein interactions is a challenge; if you
> > haven't
> > done so, please check out this paper:
> >
> > %A H. Gohlke
> > %A D.A. Case
> > %T Converging Free Energy Estimates: MM-PB(GB)SA Studies on the
> > Protein-Protein Complex Ras-Raf
> > %J J. Comput. Chem.
> > %V 25
> > %P 238-250
> > %D 2004
> >
> > ....good luck....dac
> >
> >
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--
Jason M. Swails
Quantum Theory Project,
University of Florida
Ph.D. Graduate Student
352-392-4032
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Received on Fri Oct 15 2010 - 12:00:03 PDT
