CONFORMATIONAL INVESTIGATION OF THE COFACTOR (6R,1'R,2'S-)-5,6,7,8-TETRAHYDROBIOPTERIN

(6R,1'R,2'S)-5,6,7,8-Tetrahydrobiopterin is an essential cofactor for several enzymes. Different theoretical models (molecular mechanics, se miempirical quantum chemical calculations) investigating its stereostr ucture have yielded diverging answers. To clarify these issues, combin ed molecular mechanical and ab initio quantum chemical calculations we re performed, investigating both the axial and the equatorial orientat ion of the dihydroxypropyl side-chain. After geometry optimization, th e resulting most stable structures were subjected to systematic variat ion of two side-chain torsional angles in order to study the conformat ional flexibility. The axial side-chain orientation is slightly more s table than the equatorial form. Two weak intramolecular hydrogen bonds contribute to stabilization of the axial conformer, while in the equa torial conformer only one hydrogen bond is detected. An 8 ps molecular dynamical simulation at 310 K suggests that, at realistic temperature s, the molecule is flexible enough to undergo internal motions (rotati ons, vibrations), rendering questionable the biological significance o f mere conformational properties.