Mimicking the transition state of reactions of glycoside hydrolases: Updating the conformational space of the oxocarbenium cation

Abstract

One strategy for developing glycoside hydrolase (GH) inhibitors is to mimic the conformation of the transition state (TS) along the hydrolysis reaction coordinate. We present a DFT-based model to understand the conformational space of the oxocarbenium cation as a TS in carbohydrate chemistry. Using Bolzano’s theorem, we have demonstrated the existence of a function that divides the puckering coordinate space. These results are compared with the available experimental crystal structures of GH-inhibitor complexes, and a contradictory case (GH92) was computationally studied. Our mathematical model opens a door to design more specific inhibitors and to decipher the catalytic pathways of controversial cases.

Graphical Abstract

Keywords:

• Carbohydrate
• glycoside hydrolase
• conformation
• hydrolysis mechanism
• enzymology

Notes

1 Q acts as a quick degree of freedom which means that the Q value changes automatically when a 6-ring structure changes its conformation from a chair to a boat/skew-boat. Thus, it is affecting the shape of the Cremer and Pople’s sphere (Figure 1, left), but not the 2D representation of the conformational potential/free energy surface.

2 Ideally the transition state should become planar but even if it attains a conformation close to a planar one it may be sufficient as the cost of energy for minor deformations is probably low. In this work, we assume that: 1) the planar shape is a good estimation of the transition state of the reaction, 2) even when the transition state is not planar, the reaction must cross the region where our dihedral descriptor becomes zero, so the mimic molecule used as an inhibitor will adopt a similar conformation.