I am not sure how long you are willing to wait to do the calculation, but
MMPBSA.py will be able to do QM/MM-GBSA analysis once AmberTools 1.5 is
released in the near future.
-Bill
On Thu, Mar 10, 2011 at 6:24 AM, Aust, Susanne <saust.ipb-halle.de> wrote:
>
>
> Dear Thomas,
> thank you very much for the fast answer and the long literature list!
> I calculate the average structure over the equilibrated part of the QM/MM
> MD, so I hope, I have a realistic ensemble.
>
> I try to calculate MM-GBSA and PBSA, but I got positive values for PBtot
> (for example 60.41 kcal and GBtot 2.02 kcal/mol) When I search for the
> problem in the mailing list, I could find following thread:
>
> Dear Venessa,
> > I also had similar kind of problem in past, but in my
> > case I have an Zn ion and PB is not very good in
> > dealing with ions.
> > Other thing was ion was free floating (not bound to
> > anything), therefore during calculation surface is
> > changing all the time which also gives huge error.
> > I hope this help. Or you may want to read papers about
> > how PB works
> > Thanks
>
> I think the best way is to use MM-PBSA or GBSA, but I don't know, where is
> the failure. Can I use the QM/MM-MD for the MM-GBSA calculations?
> I restraint the md simulation relatively restrictive, by reason of time,
> could there be the failure?
>
>
> Yes I know, that the Khandelwal et. al (2005)paper is due to methods not
> the best, but my boss like QM/MM calculation and Khandelwal got an r² of 0.9
> with this approach. So we try to go this way, but with the Amber forcefield.
>
> Thanks a lot!
>
> schöne Grüße aus dem frühlingshaften Deutschland :-)
> Susanne
>
>
> -----Ursprüngliche Nachricht-----
> Von: steinbrt.rci.rutgers.edu [mailto:steinbrt.rci.rutgers.edu]
> Gesendet: 10 March 2011 10:40
> An: AMBER Mailing List
> Betreff: Re: [AMBER] interaction energy
>
>
> Hi,
>
> >> I generate a average structures after md .
>
> isnt that a way of undoing what you gained from doing the MD, namely a
> realistic conformational ensemble? A single structure, even if it were the
> global energy minimum would give you an interaction energy at best, but
> you need a free energy to compare to Ki values.
>
> >> I could'nt use MM-GBSA or PBSA due to zinc in the active site.
>
> I believe it would be possible to incorporate Zn in MMPBSA. All you need
> is a reasonable ion radius. What went wrong when you tried?
>
> >> Is it possible to calculate a single QM/MM interaction energy for this
> >> type of complex in Amber ( this was done in the paper, from which I have
> >> the workflow, but they worked with the Tripos forcefield)?
>
> You could do a QM/MM minimization of your average structure and compare
> the final energies for the complexes to their Ki, but any correlation
> would probably be accidental (especially if you throw away the water
> around the complexes). There is an enormous amount of literature out there
> on protein-ligand interactions and why it is an exceptionally hard problem
> to tackle, maybe the paper you refer to is not an optimal starting point
> for what you want to do...
>
> Check out e.g.:
>
> Michel, J. Essex, J. (2008) Hit identification and binding mode
> predictions by rigorous free energy simulations. \emph{J. Med. Chem.},
> \textbf{51}, 6654--6664.
>
> Jorgensen, W. (2004) The many roles of computation in drug discovery.
> \emph{Science}, \textbf{303}, 1813--1818.
>
> Gilson, M. Zhou, H. (2007) Calculation of protein-ligand binding
> affinities. \emph{Ann. Rev. Biophys. Biomol. Struct.}, \textbf{36},
> 21--42.
>
> deAzevedo, W. Dias, R. (2009) Computational methods for calculation
> of ligand-binding affinity. \emph{Curr. Drug Targ.}, \textbf{9},
> 1031--1039.
>
> Klebe, G. (2006) Virtual ligand screening: Strategies, perspectives and
> limitations. \emph{Drug Disc. Today}, \textbf{11}, 580--594.
>
> Gohlke, H. Klebe, G. (2002) Approaches to the description and
> prediction of the binding affinity of small-molecule ligands to
> macromolecular receptors. \emph{Angew. Chem., Int. Ed.}, \textbf{41},
> 2644--2676.
>
>
> Kind Regards,
>
> Thomas
>
> Dr. Thomas Steinbrecher
> formerly at the
> BioMaps Institute
> Rutgers University
> 610 Taylor Rd.
> Piscataway, NJ 08854
>
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>
--
Bill Miller III
Quantum Theory Project,
University of Florida
Ph.D. Graduate Student
352-392-6715
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Received on Thu Mar 10 2011 - 04:00:04 PST
