Figure . a) 2D energy profile as a function of torsion angles ⍺ and β for 2, generated using 2D well-tempered metadynamics MD (WTMetaD) simulations in explicit DMSO solvent at 298 K, using GAFF parameters for DMSO and the transporter, with iodine modelled using anisotropic charge following literature protocols ( §8 in the SI). b) Representative structures for each of the minimum identified in the 2D energy profile computed independently using CREST followed by DFT optimisation at the SMD(DMSO)-ωB97X-D3/def2-QZVP// SMD(DMSO)-ωB97X-D3/def2-SVP level of theory (highlighting angles ⍺ (red) and β (blue)). Energies are reported in kcal mol -1 relative to conformer B; with energies from WTMetaD presented in parenthesis. Four energy minima (A-D) were identified in the 2D free energy landscape, corresponding to trans-(A,B) or cis-(C,D) arrangements of the two iodotriazole moieties relative to the plane of the ring (Figure ). Only the cis-arrangements allow bidentate Cl -binding, with cis-D being the most preorganised for binding due to its convergent halogen bonding groups. Representative conformers of each minimum were also identified via a dihedral-constrained search using the conformerrotamer ensemble sampling tool (CREST), followed by DFT optimisation and frequency calculations. Both MD simulations and DFT calculations indicate that all conformers are close in energy (within 2 kcal mol -1 ), with trans-B being the global minimum. The conversion from trans-B to cis-C and cis-D occurs via low energy barriers (ranging from 3 to 6 kcal mol -1 ), suggesting facile interconversion under experimental conditions. These results indicate that these macrocycles can readily adopt a convergent (cis-) geometry necessary for anion binding despite the macrocycle's strain.