Charge Determines Guest Orientation: A Combined NMR and Molecular Dynamics Study of β-Cyclodextrins and Adamantane Derivatives

Abstract

The strong binding of the adamantyl moiety to the cavity of β-cyclodextrin makes it a common binding motif in supramolecular chemistry and a common model system. Despite the attention, there are still unresolved questions regarding the orientation of the adamantane derivatives in the inclusion complexes-do they protrude from the wide or narrow opening of the cyclodextrin hosts? A combined analysis of ROESY NMR and molecular dynamics simulations allows the conclusion that positively charged adamantane derivatives are oriented with the hydrophilic group protruding from the wider opening of the cyclodextrin, while negatively charged adamantane derivatives form two coexisting types of complexes where the hydrophilic group respectively protrudes from the wide and narrow opening. Interestingly, structural modifications of the cyclodextrin host only have a slight impact on the guest orientation.

Exploring the Origins of Enthalpy–Entropy Compensation by Calorimetric Studies of Cyclodextrin Complexes

“…For complexes with natural βCD, it was recently established that the charged group of AdNH3 protrudes from the secondary rim, while AdCOO and AdCH2COO are oriented in both directions. 23 Those orientations were also observed in methylated βCDs, 23 and it seems likely that HPβCDs behave the same way. Very weak ROESY crosspeaks were observed between the protons on the AD guests and the methyl group on the HP chains of HP093, indicating limited interactions between these moieties ( Figure S5) Molecular Dynamics Simulations Molecular dynamics simulations of four of the investigated complexes were conducted to explore their structure and dynamics.…”

“…Which one is the correct guest orientation is difficult to determine experimentally, and both secondary and primary complexes may coexist, as observed for natural βCD and methylated βCDs. 23 During the 30 ns of simulation, none of the complexes dissociated. Some mobility of the guests was observed, but in all complexes the adamantyl moiety stayed inside the CD cavity.…”

Dynamic Control of the Self-Assembling Properties of Cyclodextrins by the Interplay of Aromatic and Host-Guest Interactions

“…Negatively charged hydrophilic substituents, such as the carboxylate group in AC, are not included in the hydrophobic receptacle, but it is unclear whether they protrude from the wider (type I) or the narrower rim (type II complex) (Rüdiger et al, 1996; Gómez-Biagi et al, 2008; Krishnan et al, 2012). A recent study unequivocally demonstrates that both types of complexes coexist in approximately equal amounts in the case of the inclusion complex between AC and per- O -methylated βCD (Schönbeck, 2018), but the preferred guest orientation may well-depend on the modification of the βCD platform. A comparative analysis of NOE (or ROE) contacts between the α, β and γ protons in AC and the inside located H-3 and H-5 CD protons provides an indication on this issue (Figure 13, top panel).…”

Assessment of the Physical Properties of Inclusion Complexes of Forchlorfenuron and γ-Cyclodextrin Derivatives and Their Promotion of Plant Growth

“…The H-3 proton is typically located in the wider rim of the ring of CD, and the H-6 proton is typically located in the narrower rim of that ring. 25 Cross peaks indicate that protons are less than 4 Å apart, and a more intense peak indicates that protons are closer together. 26 In the CP of CPPU and γCD (1/1), the H-3 proton (3.85 ppm), H-5 proton (3.83 ppm), and H-6 proton (3.83 ppm) in the CD cavity and the H-b proton (7.37 ppm) and H-c proton (7.42 ppm) in the aromatic ring of CPPU similarly produced cross peaks ( Figure 9 B).…”