[gmx-users] pretty large coulomb contribution to free energy

[Justin Lemkul]

On 6/26/15 4:44 PM, Ahmet Yıldırım wrote:
> Dear users,
>
> The free energy of decoupling the ligand from the complex I get is about
> 457 kcal/mol. If for ligand in solution I get -5 kcal/mol, and for the
> restraints -8 kcal/mol. Binding free energy is 457-5-8=444 kcal/mol. A
> value over 400-500 kcal/mol is not unexpected for decoupling the ligand
> from the complex? Anyone experienced similar problem? The problem is the
> intramolecular interaction of the ligand? How about this Gromacs version
> https://github.com/gromacs/gromacs/tree/022ad08b2fd0c1de085e88ac81a61841c4daea9c
> ?
>

For proper absolute binding free energies, you need these restraints.  I'm 
actually using that patched version now and it's essential for getting 
reasonable energies in protein-ligand complexes.  Otherwise you sample a ton of 
totally nonphysical configurations in (nearly) decoupled states.  Even just the 
pull code is not enough; that provides a translational restraint, but the 
orientation can vary.  See, e.g. dx.doi.org/10.1021/ci300505n for a very robust 
method that can easily be done in GROMACS now using the intermolecular bondeds.

-Justin

> Ligand I used is neutral. Gromacs version is 4.6.5
>
> Free energy control parts of my input files are below.
>
> ############ For decoupling the ligand from the complex #########
> ; Free energy control stuff
> init-lambda-state        = 5
> free_energy              = yes
> sc-alpha                 = 0.5
> sc-power                 = 1.0
> sc-sigma                 = 0.3
> restraint-lambdas        = 0.0 0.01 0.025 0.05 0.075 0.1 0.2 0.35 0.5 0.75
> 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.00 1.0 1.0 1.0 1.0 1.0 1.0
> 1.00 1.0 1.00 1.0 1.00 1.0 1.00 1.0
> coul-lambdas             = 0.0 0.00 0.000 0.00 0.000 0.0 0.0 0.00 0.0 0.00
> 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.00 1.0 1.0 1.0 1.0 1.0 1.0
> 1.00 1.0 1.00 1.0 1.00 1.0 1.00 1.0
> vdw-lambdas              = 0.0 0.00 0.000 0.00 0.000 0.0 0.0 0.00 0.0 0.00
> 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 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
> nstdhdl                  = 10
>
> pull           = umbrella
> pull_geometry  = distance
> pull_dim       = Y Y Y
> pull_start     = no
> pull_init1     = 0.2980769
>
> pull_ngroups   = 1
> pull_group0    = atom-p
> pull_group1    = atom-l
> pull_k1        = 0.0   ; kJ*mol^(-1)*nm^(-2)
> pull_kB1       = 4184  ; kJ*mol^(-1)*nm^(-2)
>
>
> ######## For solvation free energy ###########
> ; Free energy control stuff
> init-lambda-state        = 5
> free_energy              = yes
> sc-alpha                 = 0.5
> sc-power                 = 1.0
> sc-sigma                 = 0.3
> coul-lambdas             = 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.00
> 1.0 1.0 1.0 1.0 1.0 1.0 1.00 1.0 1.00 1.0 1.00 1.0 1.00 1.0
> vdw-lambdas              = 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 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
> nstdhdl                  = 10
> couple-intramol          = yes
> couple-moltype           = MOL
> couple-lambda0           = vdw-q
> couple-lambda1           = none
>
>
>

-- 
==================================================

Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow

Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Facility II, Room 629
University of Maryland, Baltimore
20 Penn St.
Baltimore, MD 21201

jalemkul at outerbanks.umaryland.edu | (410) 706-7441
http://mackerell.umaryland.edu/~jalemkul

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