Biliverdin chiral derivatives as chiroptical switches for pH and metal cation sensing

Abstract

A series of six optically active derivatives of the bile pigment biliverdin, namely (βS,β′S)-dimethylmesobiliverdin-XIIIα, cyclic esters of linear diols [HO(CH₂)_nOH] where n = 1–6, have been investigated by vibrational circular dichroism (VCD) and density functional theory (DFT) calculations. The results were correlated with the length (n) of the diester belt, the verdin helicity and an M ⇄ P conformational equilibrium – as previously shown by electronic circular dichroism (ECD). Furthermore, ECD spectra have been found to be quite sensitive to solvent nature and pH. TD-DFT calculations of the protonated/deprotonated verdins with n = 1 and 2 diester belts respectively have allowed one, moreover, to explain the spectroscopic data in terms of a change in the M ⇄ P equilibrium. Finally, the set of investigated compounds, together with other chirally functionalized “non-belted” biliverdin analogs, has also been found to be sensitive to the presence of metal ions, with which the verdins chelate. On the basis of ECD and VCD data, we propose that the spectroscopic changes observed are consistent with self-association (dimerization) of the verdin molecules promoted by the metal cations, as bolstered by DFT calculations, and for which a dimerization constant of 73 000 M⁻¹ is evaluated. We envision the use of current chiroptical spectroscopies in connection with chiral biliverdin derivatives as natural sensors or probes of the micro-environmental conditions, such as pH or the presence of metal ions.