Restraints in umbrella sampling

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1

GROMACS version:2023
GROMACS modification: No

Hi,
I have come across a question on (extra)restraints in umbrella sampling process:
will it be acceptable from a theoretical point of view, to put further position restraints (in addition to those caused by umbrella sampling pull code potential) on one of the two molecules during the main production run of an umbrella sampling simulation? this can help a more stable run esp. for large molecules like peptide fragments but doubt if this is a correct practice as i intend to use results of the umbrella sampling to derive a pair PMF between the 2 molecules. I also searched the web and noticed as an example, Justin Lemkul’s tutorial on the umbrella sampling implementation within Gromacs, in which the input file of the equlibration and also MAIN PRODUCTION run both include restraints on one the 2 group of molecules defined via topology files and called upon in .mdp file. however i still doubt is it also right to use such an EXTRA limitation on the movement of the molecules as it might effect sampling of the configuration beyond what is legitimate and accounted for in umbrella sampling formulation of restrained interactions.
Any feedback or experience regarding this subject?
rgrds

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Restraints are generally not appropriate. My situation was a special case, and the use of restraints is described and cites precedent in the associated publication. I was modeling a subset of a much larger aggregate species, so the application of a pulling force was a bit imbalanced relative to a real, physical state. I overcame that by restraining one species to mimic a much more massive species.