[gmx-users] Relative binding free energy

[Stefania Evoli]

Dear users,

I’m performing relative binding free energy calculation in Gromacs 5.0.5 of two amino acids: Alanine and Glycine. After the minimization phase the simulations crush giving me output file like 'step***.pdb' and the error is

'Fatal error:

Too many LINCS warnings (1000)

If you know what you are doing you can adjust the lincs warning threshold in your mdp file

or set the environment variable GMX_MAXCONSTRWARN to -1,

but normally it is better to fix the problem’.

Probably the problem raises when the OH appear and binds the CB. I’m using the soft-core potentials and the steep integrator as you can see in the following mdp file


; RUN CONTROL PARAMETERS

integrator               = steep

; Start time and timestep in ps

tinit                    = 0

dt                       = 0.002

nsteps                   = 2500

; mode for center of mass motion removal

comm-mode                = Linear

; number of steps for center of mass motion removal

nstcomm                  = 100 ; must be equal or larger than calcenergy

nstcalcenergy            = 100 ; Default


; CUTOFF SCHEME (default = verlet now)

cutoff-scheme           = group


; ENERGY MINIMIZATION OPTIONS

; Force tolerance and initial step-size

emtol                    = 100

emstep                   = 0.01

; Max number of iterations in relax_shells

niter                    = 20

; Step size (1/ps^2) for minimization of flexible constraints

fcstep                   = 0

; Frequency of steepest descents steps when doing CG

nstcgsteep               = 1000

nbfgscorr                = 10


; OUTPUT CONTROL OPTIONS

; Output frequency for coords (x), velocities (v) and forces (f)

nstxout                  = 0

nstvout                  = 0

nstfout                  = 0

; Checkpointing helps you continue after crashes, they are always included now

; Output frequency for energies to log file and energy file

nstlog                   = 100

nstenergy                = 100

; Output frequency and precision for xtc file

nstxout-compressed                = 0

compressed-x-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                 =

; Selection of energy groups

energygrps               =


; NEIGHBORSEARCHING PARAMETERS

; nblist update frequency

nstlist                  = 10

; ns algorithm (simple or grid)

ns_type                  = grid

; Periodic boundary conditions: xyz (default), no (vacuum)

; or full (infinite systems only)

pbc                      = xyz

; nblist cut-off

rlist                    = 1.2


; OPTIONS FOR ELECTROSTATICS AND VDW

; Method for doing electrostatics

coulombtype              = pme

rcoulomb-switch          = 0

rcoulomb                 = 1.2

; Dielectric constant (DC) for cut-off or DC of reaction field

; Method for doing Van der Waals

vdw-type                 = Cut-off

vdw-modifier             = Potential-switch

; cut-off lengths

rvdw-switch              = 0.9

rvdw                     = 1.0

; Apply long range dispersion corrections for Energy and Pressure

DispCorr                 = AllEnerPres

; Extension of the potential lookup tables beyond the cut-off

; Spacing for the PME/PPPM FFT grid

fourierspacing           = 0.10

; 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

ewald_geometry           = 3d

epsilon_surface          = 0


; OPTIONS FOR WEAK COUPLING ALGORITHMS

; Temperature coupling

Tcoupl                   = no

; Groups to couple separately

tc-grps                  = System

; Time constant (ps) and reference temperature (K)

tau_t                    = 2.0

ref_t                    = 298.15

; Pressure coupling

Pcoupl                   = no

Pcoupltype               = isotropic

; Time constant (ps), compressibility (1/bar) and reference P (bar)

tau_p                    = 1

compressibility          = 4.5e-5

ref_p                    = 1.01325


; GENERATE VELOCITIES FOR STARTUP RUN

gen_vel                  = yes

gen_temp                 = 298.15

gen_seed                 = 1993


; OPTIONS FOR BONDS

constraints              = hbonds

; Type of constraint algorithm

constraint-algorithm     = Lincs

; Do not constrain the start configuration

continuation      = no

; Use successive overrelaxation to reduce the number of shake iterations

Shake-SOR                = no

; Relative tolerance of shake

shake-tol                = 1e-04

; Highest order in the expansion of the constraint coupling matrix

lincs-order              = 12

; Number of iterations in the final step of LINCS. 1 is fine for

; normal simulations, but use 2 to conserve energy in NVE runs.

; For energy minimization with constraints it should be 4 to 8.

; Lincs will write a warning to the stderr if in one step a bond

; rotates over more degrees than

lincs-warnangle          = 30

; Convert harmonic bonds to morse potentials

morse                    = no


; ENERGY GROUP EXCLUSIONS

; Pairs of energy groups for which all non-bonded interactions are excluded

energygrp_excl           =


; Free energy control stuff

free-energy              = yes

init_lambda_state        = 0

fep_lambdas              = 0.0 0.25 0.5 0.75 1.0 1.00 1.0 1.0 1.0 1.0 1.0 1.0 1.0  1.0 1.0  1.0 1.0  1.0 1.0  1.0

vdw_lambdas              = 0.0 0.00 0.0 0.00 0.0 0.05 0.1 0.2 0.3 0.4 0.5 0.6 0.65 0.7 0.75 0.8 0.85 0.9 0.95 1.0

;couple-moltype           = LIG

;couple-lambda0           = vdw-q

;couple-lambda1           = none

;couple-intramol          = no

sc-alpha                 = 0.5

sc-sigma                 = 0.3

sc-power                 = 1.0

sc-r-power               = 6

sc-coul                  = no

nstdhdl                  = 100

calc-lambda-neighbors    = -1


I tried to modify the integrator or the soft-core parameters but nothing changed. Did someone have a problem like that? How is it possible to solve it?


Thanks,

Stefania

—
Dr. Stefania Evoli
Post-Doctoral Fellow
King Abdullah University of Science and Technology
Catalysis center - Bldg. 3, 4th floor, 4231–WS18
Thuwal, Kingdom of Saudi Arabia
stefania.evoli at kaust.edu.sa



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