Probing the Formation and Conformational Relaxation of Previtamin D₃ and Analogues in Solution and in Lipid Bilayers

Abstract

The photosynthesis of vitamin D3 in mammalian skin results from UV-B irradiation of provitamin D3 (7-dehydro­cholesterol, DHC) at ca. 290 nm. Upon return to the ground state, the hexatriene product, previtamin D3, undergoes a conformational equilibration between helical gZg and more planar tZg and tZt forms. The helical gZg forms provide a pathway for the formation of vitamin D3 via a [1,7]-sigmatropic hydrogen shift. Steady state photolysis and UV transient absorption spectroscopy are combined to explore the conformational relaxation of previtamin D3 formed from DHC in isotropic solution and confined to lipid bilayers chosen to model the biological cell membrane. The results are compared with measurements for two analogues: previtamin D2 formed from ergosterol (provitamin D2) and previtamin D3 acetate formed from DHC acetate. The resulting spectral dynamics are interpreted in the context of simulations of optical excitation energy and oscillator strength as a function of conformation. In solution, the relaxation dynamics and steady state product distributions of the three compounds are nearly identical, favoring tZg forms. When confined to lipid bilayers, the heterogeneity and packing forces alter the conformational distributions and enhance the population of a gZg conformer capable of vitamin D formation.

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…Histamine [138,393,407] Hormones Testosterone [132,408], Levothyroxine [409], Resolvins [410], Progesterone [326,327] Vitamins D2, D3 [411,412] Alcohols and product of fermentation…”

Ab Initio Simulation of the Ultrafast Circular Dichroism Spectrum of Provitamin D Ring-Opening

“…The calculation of the static CD spectrum of Pro and Pre was done using an average of 200 and 500 snapshot geometries, respectively; the lowest 10 excitation energies and rotatory strengths were used. For Pro, BOMD was used to generate the ensemble of structures, whereas for Pre, enhanced sampling using REMD was applied, as described elsewhere. ,,, For the static spectra, Gaussian line broadening was applied with a LW of 0.1 eV, yielding CD-spectra of the individual snapshot geometries. For the TRCD spectrum, a LW of 0.5 eV was applied to convert rotatory strengths to Δϵ, for both the static spectrum used as reference and the instantaneous spectrum.…”

“…In solution, this redistribution process has been found to be almost completed within tens of picoseconds to up to more than 100 ps, depending on the viscosity of the solvent. 29,32 The TDDFT-SH approach is described in detail elsewhere. 20 In brief, initial structures of Pro are obtained from a Boltzmann ensemble at room temperature, generated by Born−Oppenheimer molecular dynamics (BOMD).…”

“…The photoinduced electrocyclic ring-opening reaction of 7-dehydrocholesterol (Figure ), also known as provitamin D (Pro), has been extensively studied by time-resolved transient absorption spectroscopy in different solvents , and phospholipid bilayers. , After the ring-opening, which occurs within hundreds of femtoseconds to a few picoseconds after photoexcitation, , the formed rotationally flexible seco-steroid (seco from Latin secos, to cut, indicates that the ring of the steroid structures is cut) previtamin D (Pre) undergoes several stages of rotational isomerizations (Figure ), as nonadiabatic simulations and TRTA spectroscopy reveal. Rotational isomers of vitamin D seco-steroids are of crucial importance in the intrinsic self-regulation of vitamin D synthesis: On one hand, they give rise to a pronounced wavelength-dependent, conformationally controlled photochemistry of vitamin D derivatives. − On the other hand, rotational isomerization possibly affects the thermal formation of vitamin D via a [1,7]-sigmatropic hydrogen shift from C19 to C9, which is thought to be possible only in helical gZg Pre isomers, where hydrogen donor (C19) is in close vicinity to the acceptor atom (C9).…”

“…The rotational dephasing time amounts to approximately 4–5 ps in gas phase simulations. In solution, this redistribution process has been found to be almost completed within tens of picoseconds to up to more than 100 ps, depending on the viscosity of the solvent. , …”