Bilirubin and its congeners: conformational analysis and chirality from metadynamics and related computational methods

摘要

The conformational properties of natural bilirubin, bisbutyricmesobilirubin-XIII, and their chiral derivatives (S,S)-dimethylmesobilirubin-XIII and 8,12-(R,R)- dimethylbisbutyricmesobilirubin-XIII were investigated by metadynamics, an improved molecular dynamics computational methodology useful for conformational analysis. Applied to linear tetrapyrroles, which may be treated as two blade molecular propellers, our results are represented by conformational energy hypersurface maps built as functions of the two central dihedral torsion angles ((1) and phi(2)) following rotations of two dipyrrinone units about the connecting CH2, and are compared successfully with maps previously obtained from molecular mechanics. With an emphasis on the conformationally more flexible 8,12-(R,R)-dimethylbisbutyricmesobilirubin-XIII, a conformationally mobile optically active bilirubinoid with butyric acid replacing propionic, metadynamics reveals global and nearby minima. Its electronic circular dichroism and UV-Vis spectra predicted by DFT calculations correlate well with the experimental spectra and are explained on the basis of equilibrium between the predicted conformational energy minima.