RECONSIDERING THE CONFORMATIONAL FLEXIBILITY OF BETA-CYCLODEXTRIN

Conformational analysis of P-cyclodextrin in vacuo has been carried ou t using two complementary searching techniques to answer the question: what is the relationship between the conformational changes in the Ph i,Psi torsional angles around the glycosidic bonds and the fluctuation s of the hydroxyl pendant groups! Because of the large number of local minima on the conformation and potential energy surface of cyclodextr in, a standard systematic search involving molecular mechanics minimiz ation at points on a regular, fixed torsional angle space grid would g enerate so many points as to be impractical for conformational samplin g. Instead the RAMM (RAndom Molecular Mechanics) procedure, a molecula r mechanics calculation based on a random walk within torsional angle space, is used here and is compared to the results of nanosecond molec ular dynamics simulation. The RAMM procedure is a semi-automatic calcu lation of the n-dimensional potential energy surface of a molecule whi ch combines a grid-based conformation and search for one pair of bonds with random generation of a conformational ensemble of rotatable bond s and optimization of molecular geometry. Results are presented for si x conformers of low symmetry and three conformers with higher symmetry . For all cases, random sampling of the 287-dimensional hydroxy and hy droxymethyl pendant group torsional angle conformational space improve d the molecular energy. Torsional angles involving the primary hydroxy l groups exhibited larger conformational freedom than those involving secondary hydroxyls. The secondary hydroxyls of the symmetric forms ar e involved in a homodromic O2...O3 hydrogen bonding network. The resul ts of the RAMM modeling agree with results from molecular dynamics sim ulations at 300 K (1 ns), 400 K (2 ns), and at 1000 K(1 ns) with diele ctric constant 1. At the two lower temperatures, the molecule fluctuat es within the Phi,Psi space at values around 0 degrees,0 degrees. The occupancy profile, drawn in two-dimensional Phi,Psi plots, is similar for each of the seven combinations of Phi(i), Psi(i) and has a charact eristic half-moon shape. A stabilizing hydrogen bond network between O 2(i)...O3(i - 1) is present during the entire simulation with a conseq uent decrease in the mobility of HO2 and HO3 (oscillating around chi(i 2) congruent to -60 degrees, chi(i3) congruent to - 60 degrees). No co nformational transitions of these groups were observed at 300 K and th e first and only reorientation (chi(i2) congruent to 180 degrees, chi( i3) congruent to 180 degrees) occurred at approximately 1.7 ns at 400 K. At 1000 K, the molecule explores regions beyond Phi,Psi equal to 0 degrees,0 degrees and the chair conformer of the pyranose rings is not preserved. An additional 2 ns molecular dynamics simulation at 400 K with dielectric constant 4 revealed the ''flip-flop'' character of O2. ..O3 hydrogen bonding between adjacent glucose residues. (C) 1997 Else vier Science B.V.