The β-cyclodextrin/benzene complex and its hydrogen bonds – a theoretical study using molecular dynamics, quantum mechanics and COSMO-RS

Abstract

SummaryFour highly ordered hydrogen-bonded models of β-cyclodextrin (β-CD) and its inclusion complex with benzene were investigated by three different theoretical methods: classical quantum mechanics (QM) on AM1 and on the BP/TZVP-DISP3 level of approximation, and thirdly by classical molecular dynamics simulations (MD) at different temperatures (120 K and 273 to 300 K). The hydrogen bonds at the larger O2/O3 rim of empty β-CDs prefer the right-hand orientation, e.g., O3-H…O2-H in the same glucose unit and bifurcated towards …O4 and O3 of the next glucose unit on the right side. On AM1 level the complex energy was −2.75 kcal mol−1 when the benzene molecule was located parallel inside the β-CD cavity and −2.46 kcal mol−1 when it was positioned vertically. The AM1 HOMO/LUMO gap of the empty β-CD with about 12 eV is lowered to about 10 eV in the complex, in agreement with data from the literature. AM1 IR spectra displayed a splitting of the O–H frequencies of cyclodextrin upon complex formation. At the BP/TZVP-DISP3 level the parallel and vertical positions from the starting structures converged to a structure where benzene assumes a more oblique position (−20.16 kcal mol−1 and −20.22 kcal mol−1, resp.) as was reported in the literature. The character of the COSMO-RS σ-surface of β-CD was much more hydrophobic on its O6 rim than on its O2/O3 side when all hydrogen bonds were arranged in a concerted mode.This static QM picture of the β-CD/benzene complex at 0 K was extended by MD simulations. At 120 K benzene was mobile but always stayed inside the cavity of β-CD. The trajectories at 273, 280, 290 and 300 K certainly no longer displayed the highly ordered hydrogen bonds of β-CD and benzene occupied many different positions inside the cavity, before it left the β-CD finally at its O2/O3 side.

Binding Thermodynamics and Kinetics Calculations Using Chemical Host and Guest: A Comprehensive Picture of Molecular Recognition

“…39,40 QM/MM methods were also used to investigate the binding pose, binding enthalpy, and properties of the β -CD cavity. 41–44 In most of these studies, the conformations of β -CD resemble the crystal structures via shorter than 20 ns MD simulations and no further dynamic information from experiments or long-time-scale MD of β -CD complexes. In addition, although the binding affinity decomposition into enthalpy and entropy has been achieved for some ligands, the use of an implicit solvent model and previous computation techniques cannot obtain both solvent and solute entropy contributions that allow direct comparison with experimentally measured Δ H and Δ S .…”

Analysis of computational models of β-cyclodextrin complexes: structural studies of morniflumate hydrochloride and β-cyclodextrin complex in aqueous solution by quantitative ROESY analysis

“…The b-CD cavity assumes a symmetrical configuration in water due to the presence of hydroxyl groups on the exterior but due to the presence of several free rotating hydroxyl groups C7 symmetry may be lost. This has been observed in several studies of complexes in solid as well as in solution states [20,21]. To preserve the symmetry of b-CD in the complexes, computational studies were performed by allowing movement of only the MOR molecule while keeping bond lengths and bond angles of b-CD constant.…”

Quantitative ROESY analysis of computational models: structural studies of citalopram and β‐cyclodextrin complexes by 1H‐NMR and computational methods

“…The structures of R ‐ and S ‐CT were drawn and their geometries were minimized to root mean square gradient of 0.1 kcal/molA. The β ‐CD molecule was kept static, and only R ‐ and S ‐CT was allowed to move in all the calculations because studies in solid as well as solution state suggest that CDs adopt more symmetrical conformation in the complexes …”