From: JC Gumbart (gumbart_at_physics.gatech.edu)
Date: Thu Jun 30 2016 - 15:51:09 CDT
Hi Gabriel,
I would suggest taking a look at the following tutorial and associated papers: http://www.ks.uiuc.edu/Training/Tutorials/namd/PLB/tutorial-protein-ligand.pdf <http://www.ks.uiuc.edu/Training/Tutorials/namd/PLB/tutorial-protein-ligand.pdf>
Calculating a binding free energy can be very challenging! Particularly for a flexible ligand like ATP. And, to be honest, ABF has a great tendency to produce values that are far too high initially (due to non-equilibrium effects), then requiring potentially hundreds of ns to come back down.
Best,
JC
> On Jun 30, 2016, at 2:25 PM, Gabriel Jara <gabriel.fcq.unc.ar_at_gmail.com> wrote:
>
> Dear all,
>
> I am interested in studying the process and free energy of binding of ATP to the active site and coordinated to a magnesium. The strategy I thought was to start from the protein:ligand complex and to perform ABF simulations in order to calculate the PMF of unbinding and in this way to describe the mechanism of binding and its free energy.
>
> The problem is that I obtained huge free-energy values, ~150 kcal/mol with simulation of 80 ns. I tested different reaction coordinates, but the results are similar. At the moment, I am testing a open-conformation of the protein, in order to know the conformational effect.
>
> The reaction coordinate selected is a distance between the center of mass of the whole ligand or the nitrogenenous base or the phosphate, and a non-flexible loop in the active site. In addition, the magnesium is released from the active site along with ATP, only if I explicitly add it in the reaction coordinate.
>
> I have little experience about ABF, and I would like to know tips to overcome this issue.
>
> Following attached the collective variable file
>
>
> Colvarstrajfrequency 1000
> Colvarsrestartfrequency 1000
> colvar {
> name COMDistance
> width 0.1
> lowerboundary 7.00
> upperboundary 20.00
> lowerwallconstant 10.0
> upperwallconstant 10.0
> distance {
> group1 {
> atomnumbers { 22 23 24 25 26 27 28 29 30 31 32 33 34 35 }
> }
> group2 {
> atomnumbers { 5461 5462 5463 5464 5471 5472 5473 5474 5475 5476 5492 5493 5494 5495 5496 5497 5504 5505 }
> }
> oneSiteSystemForce yes
> }
> }
>
> abf {
> colvars COMDistance
> fullSamples 1000
> hidejacobian yes
> }
>
> Other question, is better to separate the whole reaction coordinated in several windows, similar to the next work?
>
> dx.doi.org/10.1021/ci400188q <http://dx.doi.org/10.1021/ci400188q> J.Chem.Inf.Model.2013, 53, 2376−2389
>
> Thanks in advance.
>
> Gabriel
>
>
> --
> Dr. Gabriel E. Jara
> Instituto de Química / UNICAMP
> Rua Josué de Castro s/n
> Cidade Universitária "Zeferino Vaz", Barão Geraldo
> 13083-861 Campinas, São Paulo, Brasil
> ------
>
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