A conformational study of 2-oxanol: Insight into the role of ring distortion on enzyme-catalyzed glycosidic bond cleavage

Ab initio molecular orbital theory at the G2(MP2,SVP) level has been used to study several conformations, defining part of the pseudorotational itinerary, of equatorial 2-oxanol. Half-chair (H-3(4)) and boat (B-1,B-4) transition states lie 23.7 and 14.3 kJ mol(-1) above the chair conformation (C-1(4)), respectively, while the twist-boat conformers (S-3(1) and S-5(1)) lie 6.9 and 5.9 kJ mol(-1) above the chair, respectively. Protonation of the glycosidic oxygen of the chair conformer yields an oxonium ion in the chair conformation. All other conformations collapse to give an oxocarbonium ion-water complex upon protonation. The axial anomer in the chair conformation Lies 12.0 kJ mol(-1) lower than the equatorial anomer. Protonation of the axial anomer in the chair conformation does not yield a chair, but collapses to the oxocarbonium ion. A clear role is shown for ring distortion in enzymes which perform acid-catalyzed hydrolysis of equatorial glycosides. In addition to avoiding high-energy oxonium ion intermediates, distortion of the ring also reduces the glycosidic bond-stretch energy which delays the transition state and reduces the reaction barrier. Enzymes which hydrolyze the axial anomer do not require ring distortion to achieve a concerted pathway to the oxocarbonium ion. These results are discussed in relation to three enzymes, lysozyme, neuraminidase, and beta-amylase.