Re: [AMBER] interaction energy

From: Aust, Susanne <>
Date: Thu, 10 Mar 2011 12:24:16 +0100

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 :-)

-----Ursprüngliche Nachricht-----
Von: []
Gesendet: 10 March 2011 10:40
An: AMBER Mailing List
Betreff: Re: [AMBER] interaction energy


>> 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},

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},

Kind Regards,


Dr. Thomas Steinbrecher
formerly at the
BioMaps Institute
Rutgers University
610 Taylor Rd.
Piscataway, NJ 08854

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Received on Thu Mar 10 2011 - 03:30:02 PST
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