Conformations of Steroid Hormones: Infrared and Vibrational Circular Dichroism Spectroscopy

Abstract

Steroid hormone molecules may exhibit very different functionalities based on the associated functional groups and their 3D arrangements in space, i.e., absolute configurations and conformations. Infrared (IR) and vibrational circular dichroism (VCD) spectra of four different steroid hormones, namely dehydroepiandrosterone (DHEA), 17α-methyltestosterone (MTTT), (16α,17)-epoxyprogesterone (Epoxy-P4), and dehydroepiandrosterone acetate (AcO-DHEA), were measured in deuterated dimethyl sulfoxide and some also in carbon tetrachloride. Extensive conformational searches were carried out using the recent developed conformer-rotamer ensemble sampling tool (CREST) which also accounts for solvent effects using an implicit solvation model. All the CREST conformational candidates were then reoptimized at the B3LYP-D3BJ/def2-TZVPD with the PCM of solvent. The good agreements between the experimental IR and VCD spectra and the theoretical simulations provide a conclusive information about their conformational distribution and absolute configurations. The experimental and theoretical IR and VCD spectra of AcO-DHEA in the carbonyl and alkene stretching region showed some discrepancies, and the possible causes related to solvent effects, large amplitude motions and levels of theory used in the modelling were explored in detail. As part of the investigation, additional calculations at the B3LYP-D3BJ/6-31++G (2d,p) and B3LYP-D3BJ/cc-pVTZ levels, as well as some ‘mixed’ calculations with the double-hybrid functional B2PLYP-D3 were also carried out. The results indicate that the double-hybrid functional is important for predicting the correct IR band pattern in the carbonyl and alkene stretching region.

Stereochemical Properties of Two Schiff-Base Transition Metal Complexes and Their Ligand by Using Multiple Chiroptical Spectroscopic Tools and DFT Calculations

“…Another advantage of CREST is the readily available implicit solvation models for many solvents, which can be used during a conformational search. This capability was utilized in a very recent VCD study of steroids [ 43 ].…”

Conformational Distributions of Phenyl β-D-Glucopyranoside and Gastrodin in Solution by Vibrational Optical Activity and Theoretical Calculations

“…So far, the only documented failure of CREST in producing a conformational candidate is the case of the heterochiral trimer of propylene oxide [ 29 ] whose geometry was established experimentally by rotational spectroscopic data of different isotopologues. More recently, CREST has been utilized in several VOA studies, for example, the recent report of conformations of steroid hormones by VCD [ 30 ] and the development of a computational protocol for VCD spectra of cyclic oligopeptides [ 31 ].…”