Conformations of Steroid Hormones: Infrared and Vibrational Circular Dichroism Spectroscopy.

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.

Basis Set Dependence of Optical Rotation Calculations with Different Choices of Gauge.

In this work, the basis set dependence of optical rotation (OR) calculations is examined for various choices of gauge/level of theory. The OR is calculated for a set of 50 molecules using B3LYP and CAM-B3LYP and 17 molecules using coupled cluster with single and double excitations (CCSD). The calculations employ the correlation-consistent basis sets, aug-cc-pVζZ with ζ = D, T, Q. An inverse-power extrapolation formula is then utilized to obtain OR values at the complete basis set (CBS) limit. We investigate the basis set convergence for these methods and three choices of gauge: length gauge (with gauge-including atomic orbitals, LG(GIAOs), for DFT), the origin-invariant length gauge [LG(OI)], and the modified velocity gauge (MVG). The results show that all methods converge smoothly to the CBS limit and that the LG(OI) approach has a slightly faster convergence rate than the other choices of gauge. While the DFT methods reach gauge invariance at the CBS limit, CCSD does not. The significant difference between the MVG and LG(OI) results at the CBS limit, 26%, indicates that CCSD is not quite at convergence in the description of electron correlation for this property. On the other hand, gauge invariance at the CBS limit for DFT does not lead to the same OR values for the two density functionals, which is also due to electron correlation incompleteness. A limited comparison to gas-phase experimental OR values for the DFT methods shows that CAM-B3LYP seems more accurate than B3LYP. Overall, this study shows that the LG(OI) approach with the aug-cc-pVTZ basis set for DFT, and with the CBS(DT) extrapolation for CCSD, provides a good cost/accuracy balance.

Unusual binary aggregates of perylene bisimide revealed by their electronic transitions in helium nanodroplets and DFT calculations.

The S1 ← S0 electronic transition of perylene bisimide (PBI) and its binary aggregates were investigated using a combination of helium nanodroplet isolation spectroscopy and computational methods. First, well-resolved vibronic bands of the PBI monomer obtained under the superfluid helium nanodroplet environment were compared to simulated vibronic spectra with anharmonic corrections of the band positions. Second, about ten sets of weaker vibronic bands were observed, which show similar vibronic patterns as that of the PBI monomer and have their band origins red-shifted by about 8 to 218 cm-1. Experimental Poisson curve analyses, performed at the origins of these new sets of bands and the PBI monomer, indicate that the carriers of these weaker red-shifted vibronic bands are binary adducts of PBI. Three types of PBI dimer structures where the electronic transition dipole moments of the two subunits are perpendicular to each other were proposed as possible carriers of these red-shifted vibronic patterns. Extensive vibronic simulations were carried out in a multi-step procedure with TD-DFT, vertical Hessian, and finally adiabatic Hessian approaches. Small red-shifted band origins and very similar vibronic patterns to that of the monomer were predicted for unusual, T-shaped, type I dimer structures and are in close agreement with the experimental data. The combined experimental and theoretical results indicate that the helium nanodroplet environment enables the formation of these unusual T-shaped dimers and stabilizes them.

Can One Measure Resonance Raman Optical Activity?

Resonance Raman optical activity (RROA) is commonly measured as the difference in intensity of Raman scattered right and left circularly polarized light, IR -IL , when a randomly polarized light is in resonance with a chiral molecule. Strong and sometimes mono-signate experimental RROA spectra of several chiral solutes were reported previously, although their signs and relative intensities could not be reproduced theoretically. By examining multiple light-matter interaction events which can occur simultaneously under resonance, we show that a new form of chiral Raman spectroscopy, eCP-Raman, a combination of electronic circular dichroism and circularly polarized Raman, prevails. By incorporating the finite-lifetime approach for resonance, the experimental patterns of the model chiral solutes are captured theoretically by eCP-Raman, without any RROA contribution. The results open opportunity for applications of eCP-Raman spectroscopy and for extracting true RROA experimentally.

Absolute configuration of remisporines A & B.

The absolute configuration of remisporine B was determined based on a comparison of experimental and calculated electronic circular dichroism (ECD) spectra. Density functional theory (DFT) was used to calculate the ECD spectra varying the parameter controlling the number of calculated electronic transitions. Mapping the reaction surface provided support for the proposed Diels-Alder dimerization of remisporine A to form remisporine B.

Conformational dynamics of carbohydrates: Raman optical activity of D-glucuronic acid and N-acetyl-D-glucosamine using a combined molecular dynamics and quantum chemical approach.

As two biologically and medically relevant monosaccharides, the constituents of hyaluronic acid, d-glucuronic acid and N-acetyl-d-glucosamine, constitute perfect test cases for the development of carbohydrate-specific structural methods. These two molecules have been analysed by Raman optical activity (ROA), a spectroscopic technique exhibiting exquisite sensitivity to stereochemistry. We show that it is possible to support the experiment with a simulation approach combining density functional theory (DFT) and molecular dynamics (MD), both using explicit solvation. Thus, we have gained new insight into the crucial hydration effects that contribute to the conformational dynamics of carbohydrates and managed to characterize in detail the poorly understood vibrational nature of this class of biomolecules. Experimental and calculated ROA spectra of these two molecules are reported and excellent agreement has been found. More specifically, comparison has been made with the more commonly used gas phase and implicitly solvated calculation approaches, which offer poor or zero modelling of solvent interactions. The calculated spectra have been used to resolve the structural origins of the observed bands, a current challenge in the study of carbohydrates due to a lack of definitive vibrational assignments. We report and analyse major features in the fingerprint region of the ROA spectra, with recurrent structural and spectral features between the two monosaccharides observed.

Increased accuracy of vibrational circular dichroism calculations for isotopically labeled helical peptides.

Vibrational circular dichroism (VCD) spectra have been computed with qualitatively correct sign patterns for α-helical peptides using various methods, ranging from empirical models to ab initio quantum mechanical computations. However, some details, such as deuteration effects and isotope substitution shifts and sign patterns for the resultant amide I' band shape, have remained a predictive challenge. Fully optimized computations for a 25-residue Ala-rich peptide, including implicit solvent corrections and explicit side chains that experimentally stabilize these model helical peptides in water, have been carried out using density functional theory (DFT). These fully minimized structures show minor changes in the (ϕ,ψ) torsions at the termini and yield an extra negative band to the low energy side of the characteristic amide I' couplet VCD, in agreement with experiments. Additionally, these calculations give the right sign and relative intensity patterns, as compared to experimental results, for several 13C=O substituted variants. The differences from previously reported computations that used ideal helical structures and vacuum conditions imply that inclusion of distorted termini and solvent effects can have an impact on the final detailed spectral patterns. Inclusion of side chains in these calculations had very little effect on the computed amide I' IR and VCD. Tests of constrained geometries, varying dielectric, and different functionals indicate that each can affect the band shapes, particularly for the 12C=O components, but these aspects do not fully explain the difference from previous spectral simulations. Inclusion of long-range amide coupling, as obtained from DFT computation of the full structure, or transfer of parameters from a somewhat longer peptide model, rather than shorter model, seems to be more important for the final detailed band shape under isotopic substitution. However, these corrections can also induce other changes, suggesting that previously reported, limited calculations may have been qualitatively useful due to a balance of errors. This may also explain the success of simple empirical IR models.

Experimental and theoretical polarized Raman linear difference spectroscopy of small molecules with a new alignment method using stretched polyethylene film.

This paper reports the development of the new technique of Raman linear difference (RLD) spectroscopy and its application to small molecules: anthracene and nucleotides adenosine-5'-monophosphate, thymidine-5'-monophosphate, guanosine-5'-monophosphate, and cytidine-5'-monophosphate. In this work we also present a new alignment method for Raman spectroscopy where stretched polyethylene films are used as the matrix. Raman spectra using light polarized along the orientation direction and perpendicular to it are reported. The polyethylene (PE) film spectra are consistent with powder samples and films deposited on quartz. RLD spectra determined from the difference of the parallel and perpendicular polarized light Raman spectra are also reported. The equations describing RLD are derived, and RLD spectra of anthracene and thymidine are calculated from these equations using Density Functional Theory and assuming perfect orientation of the samples. Because of the wealth of spectroscopic information in the vibrational spectra of biomolecules together with our ability to calculate spectra as a function of orientation, we conclude that RLD has the potential to provide structural information for biological samples that currently cannot be extracted from any other method.

Breakdown of the pseudopotential approximation for magnetizabilities and electric multipole moments. II. The importance of gauge invariance for large-core semi-local pseudopotentials.

In a previous paper we pointed out that core contributions to the static magnetizability are non-negligible, and can therefore lead to erroneous results within the pseudopotential approximation [P. Schwerdtfeger, B. Assadollahzadeh, U. Rohrmann, R. Schäfer, and J. R. Cheeseman, J. Chem. Phys. 134, 204102 (2011)]. In a recent paper van Wüllen showed that additional terms arising from the gauge-invariant condition for the semi-local part of a pseudopotential operator can lead to non-negligible contributions to the magnetizability tensor, which are sensitive to the gauge origin and basis set chosen [C. van Wüllen, J. Chem. Phys. 136, 114110 (2012)]. These terms were neglected in previous calculations as they were assumed to be small. In this paper we analyze the importance of the gauge-dependent semi-local pseudopotential correction term in detail for AuF and clusters of Sn showing that it leads indeed to very large corrections to the paramagnetic term for large-core pseudopotentials. Without this correction the results become very sensitive to the basis set applied. This now resolves some of the unusual large paramagnetic contributions reported before for both AuF and Sn(2).

Calculation of Raman optical activity spectra of methyl-ß-D-glucose incorporating a full molecular dynamics simulation of hydration effects.

We report calculations of the Raman and Raman optical activity (ROA) spectra of methyl-ß-D-glucose utilizing density functional theory combined with molecular dynamics (MD) simulations to provide an explicit hydration environment. This is the first report of such combination of MD simulations with ROA ab initio calculations. We achieve a significant improvement in accuracy over the more commonly used gas phase and polarizable continuum model (PCM) approaches, resulting in an excellent level of agreement with the experimental spectrum. Modeling the ROA spectra of carbohydrates has until now proven a notoriously difficult challenge due to their sensitivity to the effects of hydration on the molecular vibrations involving each of the chiral centers. The details of the ROA spectrum of methyl-ß-D-glucose are found to be highly sensitive to solvation effects, and these are correctly predicted for the first time including those originating from the highly sensitive low frequency vibrational modes. This work shows that a thorough consideration of the role of water is pivotal for understanding the vibrational structure of carbohydrates and presents a new and powerful tool for characterizing carbohydrate structure and conformational dynamics in solution.

Breakdown of the pseudopotential approximation for magnetizabilities and electric multipole moments: test calculations for Au, AuF, and Sn(n) cluster (n ≤ 20).

The response of the electronic wavefunction to an external electric or magnetic field is widely considered to be a typical valence property and should, therefore, be adequately described by accurately adjusted pseudopotentials, especially if a small-core definition is used within this approximation. In this paper we show for atomic Au and Au(+), as well as for the molecule AuF and tin clusters, that in contrast to the case of the static electric dipole polarizability or the electric dipole moment, core contributions to the static magnetizability are non-negligible, and can therefore lead to erroneous results within the pseudopotential approximation. This error increases with increasing size of the core chosen. For tin clusters, which are of interest in ongoing molecular beam experiments currently carried out by the Darmstadt group, the diamagnetic and paramagnetic isotropic components of the magnetizability tensor almost cancel out and large-core pseudopotentials do not even predict the correct sign for this property due to erroneous results in both the diamagnetic and (more importantly) the paramagnetic terms. Hence, all-electron calculations or pseudopotentials with very small cores are required to adequately predict magnetizabilities for atoms, molecules and the solid state, making it computationally more difficult to obtain this quantity for future investigations in heavy atom containing molecules or clusters. We also demonstrate for this property that all-electron density functional calculations are quite robust and give results close to wavefunction based methods for the atoms and molecules studied here.

Optical rotatory dispersion of 2,3-hexadiene and 2,3-pentadiene.

The specific rotation of (P)-2,3-hexadiene (1) was measured as a function of wavelength for the gas phase, the neat liquid, and solutions. There was a surprisingly large difference between the gas phase and condensed phase values. The specific rotation was calculated using B3LYP and CCSD, and the difference in energy between the three low energy conformers was estimated at the G3 level. The Boltzmann-averaged CCSD-calculated rotations using the gauge independent velocity gauge representation, as well as the B3LYP values, are in agreement with the gas-phase experimental values. In order to avoid possible problems associated with the conformers of 1, 2,3-pentadiene (2) also was examined. Here again, there was a large difference between the gas-phase and condensed-phase specific rotations, with the CCSD velocity gauge (and B3LYP) results being close to the gas-phase experimental values. The possibility that 2,3-pentadiene could be distorted on going from the gas to liquid phase, thereby accounting for the effect of phase on the specific rotation, was examined via a Monte Carlo statistical mechanics simulation. No effect on the geometry was found. Specific rotations of 1 found in solutions were similar to those for the liquid phase, indicating that the phase difference was not due to association.

Polarizable Embedding Approach for the Analytical Calculation of Raman and Raman Optical Activity Spectra of Solvated Systems.

We present an analytical formulation and implementation of Raman and Raman Optical Activity (ROA) spectra within a three-layer fully polarizable Quantum Mechanical (QM)/ Molecular Mechanics (MM)/Polarizable Continuum Model (PCM) approach. Polarization effects in the MM layer are modeled by exploiting the Fluctuating Charges (FQ) method, in which MM solvent atoms are endowed with electric charges that can be mutually polarized by the solute QM density. Because of its fully polarizable atomistic description, QM/FQ/PCM is able to account for specific solvent effects like those due to hydrogen bonds, providing a physical picture for protic solvents such as water. Applications to aqueous (R)-methyloxirane and (S)-methyllactate are presented, and results are compared with available experimental data.

Basis Set Dependence of Vibrational Raman and Raman Optical Activity Intensities.

We present a systematic study of the basis set dependence of the backscattering vibrational Raman intensities and Raman Optical Activity (ROA) intensity differences. The accuracies of computed Raman intensities and ROA intensity differences for a series of commonly used basis sets are reported, relative to large reference basis sets, using the B3LYP density functional. This study attempts to separately quantify the relative accuracies obtained from particular basis set combinations: one for the geometry optimization and force field computation and the other for the computation of Raman and ROA tensors. We demonstrate here that the basis set requirements for the geometry and force fields are not similar to those of the Raman and ROA tensors. The Raman and ROA tensors require basis sets with diffuse functions, while geometry optimizations and force field computations typically do not. Eleven molecules were examined: (S)-methyloxirane, (S)-methylthirane, (R)-epichlorhydrin, (S)-CHFClBr, (1S,5S)-α-pinene, (1S,5S)-ß-pinene, (1S,4S)-norborneneone, (M)-σ-[4]-helicene, an enone precursor to a cytotoxic sesquiterpene, the gauche-gauche conformer of the monosaccharide methyl-ß-d-glucopyranose, and the dipeptide Ac-(alanine)2-NH2. For the molecules examined here, intensities and intensity differences obtained from Raman and ROA tensors computed using the aug-cc-pVDZ basis set are nearly equivalent to those computed with the larger aug-cc-pVTZ basis set. We find that modifying the aug-cc-pVDZ basis set by removing the set of diffuse d functions on all atoms (while keeping the diffuse s and p sets), denoted as aug(sp)-cc-pVDZ, results in a basis set which is significantly faster without much reduction in the overall accuracy. In addition, the popular rDPS basis set introduced by Zuber and Hug offers a good compromise between accuracy and efficiency. The combination of either the aug(sp)-pVDZ or rDPS basis for the computation of the Raman and ROA tensors with the 6-31G* basis set for the geometry optimization and force field calculation is a reliable and cost-effective method for obtaining Raman intensities and ROA intensity differences.

Effect of substituents and conformations on the optical rotations of cyclic oxides and related compounds. relationship between the anomeric effect and optical rotation.

The effect of substituents on the specific rotation of substituted cyclic oxides (X = F, Cl, CN, and HCC) and related compounds was studied via geometry optimization at the B3LYP/6-311+G** level followed by calculations of the specific rotation with B3LYP/aug-cc-pVDZ and, when practical, also with B3LYP/aug-cc-pVTZ. In some cases chiral samples were prepared so that the calculated specific rotations could be compared with experimental data. With most compounds there was only a minor effect of the basis set on the specific rotations. With the oxiranes and oxetanes, the chloro derivative gave a different behavior than the other substituents, but all substituents behaved in the same fashion with trans-2-methyl-1-X-cyclopropanes. Therefore the unusual behavior of chlorooxirane probably results from an interaction between oxygen and chlorine rather than being due to the presence of a three-membered ring. Chlorine is also an unusual substituent for the tetrahydrofurans. The effect of conformation on the calculated specific rotations was examined with the axial and equatorial 2-substituted tetrahydropyrans, where the anomeric effect is operative with the axial substituent, and also the 3-substituted tetrahydropyrans that would not be subject to the anomeric effect. The unusual effect of chlorine was seen only when it is antiperiplanar with respect to the oxygen.

Conformational spaces of the gastrointestinal antisecretory chiral drug omeprazole: stereochemistry and tautomerism.

A study of the conformational spaces of the chiral proton pump inhibitor (PPI) drug omeprazole by semiempirical, ab-initio, and DFT methods is described. In addition to the chiral center at the sulfinyl sulfur atom, the chiral axis at the pyridine ring (due to the hindered rotation of the 4-methoxy substituents) was considered. The results were analyzed in terms of the 5-methoxy and 6-methoxy tautomers and the two pairs of enantiomers (R,P)/(S,M) and (R,M)/(S,P). Five torsion angles were systematically explored: the backbone rotations defined by D1 (N3-C2-S10-O11), D2 (C2-S10-C12-C13), and D3 (S10-C12-C13-N14) and two methoxy rotations defined by D4 (C6-C5-O8-C9) and D5 (C16-C17-O19-C20). Significant energy differences were revealed between the 5- and 6-methoxy tautomers, the extended and folded conformations, and the (S,M) and (S,P) diastereomers. The "extended M" conformation of the 6-methoxy tautomer of (S)-omeprazole was found to be the most stable conformer.

Calculation of Nuclear Spin-Spin Coupling Constants of Molecules with First and Second Row Atoms in Study of Basis Set Dependence.

This paper proposes a systematic way to modify standard basis sets for use in NMR spin-spin coupling calculations, which allows the high sensitivity of this property to the basis set to be handled in a manner which remains computationally feasible. The new basis set series is derived by uncontracting a standard basis set, such as correlation-consistent aug-cc-pVTZ, and extending it by systematically adding tight s and d functions. For elements in different rows of the periodic table, different progressions of functions are added. The new basis sets are shown to approach the basis set limit for calculations on a range of molecules containing hydrogen and first and second row atoms.

Sum-over-states calculation of the specific rotations of some substituted oxiranes, chloropropionitrile, ethane, and norbornenone.

A sum-over-states approach has been applied to the calculation of the specific rotations of several substituted oxiranes, 2-chloropropionitrile, and 30 degrees-rotated ethane. In each case, the first few excited states proved to have only a relatively small effect on the calculated specific rotation. It was necessary to use a very large number of excited states in order to achieve convergence with the results of the more direct linear response method. However, the latter does not give information on which excited states are important in determining the specific rotation. Norbornenone is unique in that its greatly enhanced specific rotation as compared to norbornanone is associated with the low-energy n-pi* transition. The C=C bond orbitals interact with the C=O in the LUMO, and a density difference plot for going from the ground state to the first excited state clearly shows the perturbation of the C=C.

Conformational effects on optical rotation. 2-Substituted butanes.

The specific rotations of 2-substituted butanes (X = F, Cl, CN, and HCC) were calculated at the B3LYP/aug-cc-pVDZ level as a function of the C-C-C-C torsion angle. The results for the four compounds are remarkably similar, despite large differences in the electronic transition energies. The temperature dependence of the specific rotations for 2-methylbutyronitrile and for 2-chlorobutane was studied to give experimental information about the effect of the torsion angle on the specific rotation. The results were in good accord with B3LYP/aug-cc-pVDZ calculations. The specific rotations derived from the study of 2-chlorobutane are similar to those previously obtained for 3-chloro-1-butene, indicating that the double bond does not have a large effect on the optical rotations, but it did lead to a large difference between calculated and observed specific rotations.

Chiroptical properties of 2-chloropropionitrile.

(S)-(-)-2-chloropropionitrile has been prepared from (S)-(+)-alanine, and the ORD curves have been obtained in several solvents and in the gas phase. A reaction field extrapolation of the solution data to the gas phase led to an estimated value of [alpha]D = -21 degrees, whereas the interpolated gas phase value is -8 degrees. The specific rotation was found to be temperature dependent in ethylcyclohexane solution over the range 0-100 degrees C. Although rotation of the methyl group leads to large calculated effects on the specific rotation, it does not lead to the temperature dependence. Rather, a low frequency mode at 224 cm(-1) was found to be responsible. This is a mixed mode involving methyl torsion and C-C[triple bond]N bending. The specific rotations calculated at the B3LYP/aug-cc-pVDZ level including electric field dependent functions are in very good agreement with the measured gas phase values.