Conformational flexibility of sulphur linked saccharides a possible key to their glycosidase inhibitor activity

Abstract

We investigate the reasons why sulphur linked saccharides are good inhibitors of retaining β-glycosidases. A comparison of the conformational space and electronic profile of the oxygen and sulphur linked oligosaccharides using HF/6-31G* * reveals that they are electronically very similar and have identical conformational preferences. However, the conformational barriers separating the minima are at least 3 kcal mol− 1 lower for the sulphur linkage implying a greater conformational flexibility. Furthermore, we find using natural bond orbital analysis that the sulphur linkage is significantly less open to acid hydrolysis than the oxygen, found in the natural sugar on which retaining β-glycosidases act. Our nanosecond molecular dynamics studies of Bacillus agaradhaerens glycosidase reveal that the thio-cellotriose binds the enzyme 6 kcal mol− 1more strongly than does cellotriose. A comparison of the conformational space of the sulphur linkage with that of the oxygen glycosidic linkage provides an explanation for the stronger binding which appears to be due to the greater flexibility of the sulphur glycosidic linkage.