Very high solvation free energy value

User discussions
1

Dear gromacs users,

I am running an alchemical free energy calculation using the free energy perturbation method for calculating the solvation free energy for solvating an organic molecule in ethylene-glycol.

For alchemical free energy calculation I have used energy minimization, NVT equilibration and velocity generation, NPT equilibration and then production run, at each lambda values. Following are my mdp file setting for free-energy calculation: (I am using gromacs 2024, sd integrator and C-rescale barostat)

free_energy = yes
init_lambda_state = 20
delta_lambda = 0
calc_lambda_neighbors = 1 ; only immediate neighboring windows
couple-moltype = Merocyanine ; name of moleculetype to decouple
couple-lambda0 = none ; vdw and coulomb interactions are turned off for lamda=0
couple-lambda1 = vdw-q ; turn on vdw and coulomb interactions for lambda=1
couple-intramol = yes
; Vectors of lambda specified here
; Each combination is an index that is retrieved from init_lambda_state for each simulation
; init_lambda_state 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
vdw_lambdas = 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00
coul_lambdas = 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00
fep_lambdas = 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00
; Options for the decoupling
sc-alpha = 0.5
sc-coul = no ; linear interpolation of Coulomb (none in this case)
sc-power = 1
sc-sigma = 0.3
nstdhdl = 10

I have kept couple-intramol = yes as setting it to “no” was generating many errors related to pair interactions and setting this to yes is not throwing any errors, I ran the NVT and NPT equilibrations (with alchemical setup) for 500 ps each and the production MD for 1 ns.

When I am running gmx bar I am getting overall free energy change is -320 kJ/mol approximately. Now this is extremely large value, my question is does this value make any sense or any problem is there with my simulation settings? Any help is much appreciated, thank you

2

This is a reasonable order of magnitude for a molecule of that size. I suggest that you read up on some literature or typical solvation free-energy values for similar molecules before asking questions here. As a scientist, which I assume you are, you should have an idea of the order of magnitude of an answer for a calculation you are performing.