we all know rapa is a macrocyclic compound…
https://pubs.acs.org/doi/10.1021/acs.jcim.0c00025
experimental torsional-angle preferences in ETKDG are currently only for acyclic bonds. Therefore, we aim in this study to expand ETKDG for improved sampling of both small and large aliphatic rings. For molecules with small rings, we have developed additional torsional-angle potentials derived from the CSD [(38)](javascript:void(0)
to describe the preferences of aliphatic cyclic bonds, analogous to those for acyclic bonds. For efficient sampling of macrocyclic conformers, we introduce customizable heuristics based on geometric and non-bonded interactions in order to bias the sampling toward specific regions of conformational space. The use of heuristics has been found previously to improve the generation of relevant conformational ensembles. [(25,26)](javascript:void(0)