[gmx-users] Calculating Binding Affinity between Protein and Ligand using FEP

[sunita gupta]

Hello all

Earlier also I posted a query regarding FEP for protein ligand complex, but
I dint not help much.
Again I would like to share detailed information regarding the protocol I am
following for calculation the binding free energy between protein and ligand
using FEP(free energy perturbation) method. Please correct me if I am wrong
anywhere....as the values of *dVpot/dlambda  dEkin/dlambda  dG/dl constr *are
continuously coming zero(0).

I followed the gromacs tutorial of protien-ligand complex (
http://cinjweb.umdnj.edu/~kerrigje/pdf_files/trp_drug_tutor.pdf) for
preparing the coordinate and topology file for the whole system.
For Free energy Calculation I followed the tutorial (
http://www.dillgroup.ucsf.edu/group/wiki/index.php/Free_Energy:_Tutorial)
for lambda value ranging from zero(0) to 1 and setup 11 independent job for
each lambda value for 5 ns.
But the* dVpot/dlambda  dEkin/dlambda  dG/dl constr* values in the *.log are
continuously coming zero.
Any help will be highly appreciated.

For convenience I am also pasting my pro_constV.mdp (please let me know if
any parameter is wrong of missing...which is leading to such problem)

; RUN CONTROL PARAMETERS =
integrator               = md
; start time and timestep in ps =
tinit                    = 0
dt                       = 0.002
nsteps                   = 5000000
; number of steps for center of mass motion removal =
nstcomm                  = 100
; OUTPUT CONTROL OPTIONS =
; Output frequency for coords (x), velocities (v) and forces (f) =
nstxout                  = 50000
nstvout                  = 50000
nstfout                  = 0
; Output frequency for energies to log file and energy file =
nstlog                   = 500
nstenergy                = 500
energygrps               = protein non-protein
; Output frequency and precision for xtc file =
nstxtcout                = 5000
xtc-precision            = 1000
; This selects the subset of atoms for the xtc file. You can =
; select multiple groups. By default all atoms will be written. =
;xtc_grps                 =
; NEIGHBORSEARCHING PARAMETERS =
; nblist update frequency =
nstlist                  = 10
; ns algorithm (simple or grid) =
ns_type                  = grid
; Periodic boundary conditions: xyz or none =
;pbc                      = xyz
; nblist cut-off         =
rlist                    = 1.0
;domain-decomposition     = no
; OPTIONS FOR ELECTROSTATICS AND VDW =
; Method for doing electrostatics =
coulombtype              = pme
;rcoulomb-switch          = 0
rcoulomb                 = 1.0
; Dielectric constant (DC) for cut-off or DC of reaction field =
epsilon-r                = 1
; Method for doing Van der Waals =
vdw-type                 = cut-off
; cut-off lengths        =
;rvdw-switch              = 0.8
rvdw                     = 1.4
; Apply long range dispersion corrections for Energy and Pressure =
DispCorr                  = EnerPres
; Spacing for the PME/PPPM FFT grid =
fourierspacing           = 0.1
; FFT grid size, when a value is 0 fourierspacing will be used =
fourier_nx               = 0
fourier_ny               = 0
fourier_nz               = 0
; EWALD/PME/PPPM parameters =
pme_order                = 6
ewald_rtol               = 1e-06
epsilon_surface          = 0
optimize_fft             = yes
;restraints
;dihre=yes
;dihre-fc=1
;nstdihreout=1000
;disre=simple
;disre_fc=1
; Berendsen temperature coupling is on
Tcoupl = berendsen
tau_t = 0.1 0.1
tc_grps = protein non-protein
ref_t = 300 300
;OPTIONS FOR PRESSURE COUPLING
Pcoupl                   = berendsen
tau_p                    = 0.5
compressibility          = 4.5e-05
ref_p                    = 1.0
; Free energy control stuff
free_energy              = yes
init_lambda              = 0.0
delta_lambda             = 0
sc_alpha                 = 0.5
sc-power                 = 1.0
sc-sigma                 = 0.3
; GENERATE VELOCITIES FOR STARTUP RUN =
gen_vel                  = yes
gen_temp                 = 300
gen_seed                 = 173529
; OPTIONS FOR BONDS     =
constraints              = hbonds
; Type of constraint algorithm =
constraint-algorithm     = Lincs
; Do not constrain the start configuration =
unconstrained-start      = no
; Relative tolerance of shake =
shake-tol                = 0.0001
; Highest order in the expansion of the constraint coupling matrix =
lincs-order              = 12
; Lincs will write a warning to the stderr if in one step a bond =
; rotates over more degrees than =
lincs-warnangle          = 30



-- 
Best Regards
SUNITA GUPTA
Member Research Team
LeadInvent Technology
TBIU, IIT Delhi, India
Email- sunita at leadinvent.com
Ph- +9111 26581524 (Ex-6)
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