# Free energy perturbation - mdp parameters

**URL:** <https://gromacs.bioexcel.eu/t/free-energy-perturbation-mdp-parameters/2061>\
**Category:** User discussions\
**Tags:** mdp-parameters, free-energy\
**Created:** [April 29, 2021, 8:23am UTC](https://gromacs.bioexcel.eu/t/free-energy-perturbation-mdp-parameters/2061 "2021-04-29T08:23:37Z")\
**Posts on this page:** 3\
**Page:** 1

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**Author:** ![galmasrati](https://avatars.discourse-cdn.com/v4/letter/g/b9e5f3/32.png) [@galmasrati](https://gromacs.bioexcel.eu/u/galmasrati)\
**Post date:** [April 29, 2021, 8:23am UTC](https://gromacs.bioexcel.eu/t/free-energy-perturbation-mdp-parameters/2061/1 "2021-04-29T08:23:37Z")

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GROMACS version: 2019  
GROMACS modification: No

Hi GROMACS users,  
I’m new to free energy perturbation and I would greatly appreciate your input. In a nut shell, I wish to alchemically transform an aspartate in a protein’s binding site from de-protonated to protonated sate (the ligand - an ion - does not changes). For this purpose I produced a hybrid protein structure and topology using the pmx server.

First, as this is quite a large system (protein+membrane+solvent), is it legit to equilibrate the system once and then replicate it with the different lambda values in the mdp file, dropping the first x-ns of production for the final analysis?

Second, I would appreciate some input on the following mdp options (a complete mdp file is also attached):

_couple-moltype_, _couple-lambda0_ and _couple-lambda1_: I left these options empty. The gromacs manual implies one cannot use both hybrid topologies and these mdp file options. Is this the case?

_couple-intramol = yes_: becauese the molecular structure changes (protonation state).

_mass\_lambdas_ and _bonded-lambdas_: as I’m adding a hydrogen atom to my aspartate residue I’m assuming I should set these two options alongside the coul-lambdas and vdw-lambdas. I intend to first decouple the coulombic interactions and then vdw. When should the mass and bonded interactions be decoupled? Parallel to vdw?

_sc-coul = no_: In equilibrium alchemical free energy calculation only the van der Waals interactions need to be soft-cored. Right?

Any help would be much appreciated!

Cheers,  
Gal.

[fep.mdp](https://gromacs.bioexcel.eu/uploads/short-url/wpUrPA7P3pgVuPIqqjEvHthNQHr.mdp) (4.2 KB)

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**Author:** ![hess](https://dub1.discourse-cdn.com/flex017/user_avatar/gromacs.bioexcel.eu/hess/32/416_2.png) [@hess](https://gromacs.bioexcel.eu/u/hess)\
**Post date:** [April 30, 2021, 9:45am UTC](https://gromacs.bioexcel.eu/t/free-energy-perturbation-mdp-parameters/2061/2 "2021-04-30T09:45:03Z")

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The couple parameters are for solvation free-energies, you don’t need those.

Avoid changing masses if you can, then you don’t need mass-lambdas either.

Are you planning to do the whole changes in a single lambda path? Then you need to couple the bondeds and sc-coul=yes, as you are growing a hydrogen, I assume with charge. Note that in thi, s case it is simpler to do everything with a single lambda setupwithout the lambda for interaction types.

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**Author:** ![galmasrati](https://avatars.discourse-cdn.com/v4/letter/g/b9e5f3/32.png) [@galmasrati](https://gromacs.bioexcel.eu/u/galmasrati)\
**Post date:** [May 2, 2021, 8:53am UTC](https://gromacs.bioexcel.eu/t/free-energy-perturbation-mdp-parameters/2061/3 "2021-05-02T08:53:46Z")

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Hi hess, thanks for replying!

I am planning on doing the whole changes in a single lambda path.  
I’m not sure I understand what you mean by “do everything with a single lambda”. Do you mean using _fep-lambdas_ instead of _coul/vdw_ etc? or is it something else?

Cheers,  
Gal.