Conformational analysis of sterols: comparison of X-ray crystallographic observations with data from other sources.

Cystallographic data on over 400 steroids collected in the Atlas of Steroid Structure provide information concerning preferred conformations, relative stabilities and substituent influence of the interactive potential of steroid hormones. Analysis of these data indicates that observed conformational details are intramolecularly controlled and that the influence of crystal packing forces is negligible. Crystallographic data on the orientation of the progesterone side chain contradict published force-field calculations. In 84 of 88 structures having a 20-one substituent, the C(16)-C(17)-C(20)-O(20) torsion angle is between 0 degrees and -46 degrees. The 4 torsion angles that lie outside this range do so because of a 16 beta-substituent and not because of crystal packing forces. Not one of the 88 structures is found to have a conformation in which the C(16)-C(17)-C(20)-O(20) torsion angle is within +/- 15 degrees of the most commonly calculated minimum energy value. The narrow range of side chain conformations seen in very different crystalline environments in the 88 crystal structure determinations and the predictable substituent influence apparent in the data strongly suggest that crystallographically observed conformers seldom deviate from minimum energy positions, regardless of hypothetical broad energy minima, metastable states and small barriers to rotation. The 96 crystallographically independent determinations of the cholestane 17-side chain show that the chain has 4 principal conformations (A:B:C:D), occurring in the ratio 69:8:8:11. Although the fully extended side chain is clearly the energetically most favored one, in 16 observations of cholesterol itself only 6 are in the extended conformation. Some of the correlated conformational changes in the chains can be rationalized on the basis of model studies, but others apparently result from subtle intramolecular forces. The unsaturated B ring provides another element of flexibility in the structure of cholesterol. The 5-ene B ring is normally observed in an 8 beta, 9 alpha-half-chair conformation. However, in structures containing more than one molecular in the crystallographic asymmetric unit, at least one of the 2 molecules is found to differ significantly from this form. It may be that this inherent flexibility is responsible for the presence of conformationally distnct molecules in the same crystal. The intermolecular interaction observed in the crystal structure of cholesterol and its fatty acid derivatives illustrate the type of interaction between the steroid ring system and hydrocarbon chains that can be expected in membrane bilayers.