From: Shailesh Pandey (shaileshp51_at_gmail.com)
Date: Mon Sep 01 2014 - 07:31:34 CDT
Dear all,
I have performed MD simulation with explicit water of receptor(P),
ligand(L) and complex(PL) each of hundreds of ns, now I want to calculate
binding energy using MMPB(GB)SA combined with quasiharmonic approach for
considering entropic contribution:
delta(G) = delta(H) - T delta(S) = delta(Emm) + delta(Gpb/gb) + delta(Gsa)
– T delta(S)
Firstly, I tried to use single trajectory protocol for calculation with GB,
with this approach delta(Emm) is ~zero
I used GB implemented in NAMD with following set of parameters for
delta(Emm) + delta(Gpb/gb) = E_complex – (E_receptor + E_ligand),
where E_x is different bonded(bonds, angle, dihed, improp) and
non-bonded(electrostatics, vdw) energy components.
# parameters are as below
structure complex_nowater.psf
paraTypeCharmm on
parameters par_all27_prot_lipid_na.inp
numsteps 1
outputname namd-pept-temp
temperature 0
COMmotion yes
dielectric 1.0
#######################################################################
gbis on
alphaCutoff 12.0
ionConcentration 0.000002
# Force-Field Parameters
exclude scaled1-4
1-4scaling 1.0
cutoff 14.0
switching on
switchdist 13.0
pairlistdist 16.0
nonbondedFreq 1
sasa off
################## Specific to system Complex ##########
pairInteraction on
pairInteractionGroup1 1
pairInteractionFile namd-cplx-temp.pdb
pairInteractionSelf on
coordinates namd-cplx-temp.pdb
coorfile open dcd namd-cplx-temp.dcd
#+++++++++++++++ Specific to ligand ####################
pairInteraction on
pairInteractionGroup1 1
pairInteractionFile namd-pept-temp.pdb
pairInteractionSelf on
coordinates namd-pept-temp.pdb
coorfile open dcd namd-pept-temp.dcd
#++++++++++++++ Specific to protein #####################
pairInteraction on
pairInteractionGroup1 1
pairInteractionFile namd-prot-temp.pdb
pairInteractionSelf on
coordinates namd-prot-temp.pdb
set ts 0
coorfile open dcd namd-prot-temp.dcd
################## COMMON FOR ALL CASES ############
set ts 0
while { ![coorfile read] } {
firstTimestep $ts
run 0
incr ts 1
}
coorfile close
for all the systems complex trajectory contained 100 frames collected after
2ns equilibration.
and statistics for delta(Emm) + delta(Ggb) is
Min. :5481
1st Qu. :5572
Median :5622
Mean :5638
3rd Qu. :5714
Max. :5875
Even if i include SASA contribution which is around -14 kcal/mol.
Above value is so much positive, ie. delta(H) ~ 5500 kcal/mol, indicating
some problem,
compensation of so much delta(H) with entropy does not looks realistic,
although i have not yet included entropic contribution
Experimental Kd value is ~13microM
I searched namd mailing list, found some post but I could not sort it out.
e.g
http://www.ks.uiuc.edu/Research/namd/mailing_list/namd-l.2011-2012/4135.html
Most possibly I am making some mistake in above delta(H) calculation using
GBSA approach, I will be grateful for any help this regard.
Thanks & Regards
Shailesh Pandey
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