unbinding free energy using ABF

From: Gabriel Jara (gabriel.fcq.unc.ar_at_gmail.com)
Date: Thu Jun 30 2016 - 13:25:27 CDT

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 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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