Inclusion of citral isomers in native and methylated cyclodextrins: Structural insights by X-ray crystallography and molecular dynamics simulation analysis

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The crystal structure of the inclusion compounds of citral (cr) isomers in native α- and β-Cyclodextrin (α-CD and β-CD) as well as in heptakis(2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD) and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin (TM-β-CD) have been explicitly investigated by X-ray crystallography and molecular dynamics (MD) simulations.The cr/α-CD complex unit, with a 1:2 guest:host stoichiometry, consists of a head-to-head type α-CD dimer encapsulating either an E- or a Z-citral isomer with occupancy of 0.4 and 0.6 respectively. In the case of the cr/β-CD, head-to-head β-CD dimers are also formed, hosting two highly disordered guest molecules, both being E-citral isomers (2:2 guest:host stoichiometry). MD simulations based mainly on the determined crystal structures, show that the formed inclusion complexes are stable in a simulated aqueous environment and that Z-citral has the tendency to adopt a more ‘bent’ conformation than E-citral upon encapsulation in the hydrophobic CD cavity. MM/GBSA-calculations clearly indicate a higher binding affinity in the case of the cr/α-CD than the cr/β-CD inclusion complex.The inclusion complexes of citral in DM-β-CD and TM-β-CD both crystallize with a 1:1 guest:host stoichiometry. Only the E-citral isomer is found inside the DM-β-CD with its aldehyde group protruding from the narrow rim of the host, whereas both E- and Z-citral isomers, with occupancy of 0,7 and 0,3 respectively, are present in the TM-β-CD accommodated with different modes inside the host's cavity. MD simulations in aqueous environment reveal a stable inclusion complex of citral in DM-β-CD and a rather unstable in TM-β-CD, the ascending order of the binding affinities of these inclusion complexes as estimated by MM/GBSA calculations being: Z/TMβCD < E/TMβCD < E/DMβCD.It is noticed that in the crystalline state, the rigid cavity of β-CD and DM-β-CD favors the inclusion of the E-citral which adopts an extended conformation and is accommodated ‘axially’ in it, whereas the Z-citral isomer, that adopts a more bent conformation upon encapsulation in the hydrophobic CD cavity, is found only in the case of the cr/α-CD where the 1:2 guest:host stoichiometry provides the space to accommodate the bent Z-citral and in the case of the cr/TM-β-CD complex, where the bent Z-citral is found accommodated ‘equatorially’ near the wide secondary rim of the distorted host.