Carbohydrates are immensely important to almost every aspect of known life. Not only are they central metabolites in energy storage and transport (e.g. cellulose), they are frequently present as covalent attachments on cells and proteins in eukaryotes and have specific roles in a variety of biological processes. The enzymes responsible for their formation and degradation (glycosyltransferases, GTs and glycoside hydrolases, GHs) are of growing importance as drug targets. Alterations in the functioning of these enzymes lead to diseases such as AIDS, influenza, diabetes, asthma and some types of cancer, as well as rare diseases such as the so-called lysosomal storage diseases. Finding molecules that selectively block specific GTs and GTs and developing therapeutic probes for diagnosis are very active fields of research. In the last years, our group has developed efficient approaches to decipher the molecular mechanisms of carbohydrate-active enzymes by means of first principles molecular dynamics simulations. In this project, we aim to use these methods to identify the conformational itinerary and reaction mechanisms of glycosyltransferase enzymes involved in two of the most common lysosomal storage diseases, Gaucher and Fabry disease, as well as and design inhibitors able to block the enzyme’s activities.

The research group “Quantum simulation of biological processes” is internationally known in the field of computational glycobiology for their work on the dissection of the mode of action of carbohydrate processing enzymes at atomic detail using quantum mechanics/molecular mechanics (QM/MM) and molecular dynamics (MD) techniques and the PI has received several recent awards for this work (including ERC Synergy Grant 2020). The group is actively involved in many multi-disciplinary collaborative projects with experimental groups worldwide. The PhD candidate is expected to perform secondments at other European laboratories.

The main objective of the project is the rational design of inhibitors for enzymes involved in Gaucher and Fabry diseases.  The enzymes β-glucosyltransferase and a-galactosyltransferase, responsible for the synthesis of the carbohydrates that accumulate in these diseases, will be explored by means of quantum mechanics/molecular mechanics (QM/MM) simulations, in which the group has a large and successful experience. The electronic and structural properties of the transition state (TS) of the reaction will be analyzed and small molecule inhibitors will be proposed that match these properties and their degree of TS mimicry will be optimized. These investigations will be extended to glycoside hydrolase enzymes directly responsible of Gaucher and Fabry syndromes (glucocerebrosidase and α-galactosidase, respectively), in order to design chemical probes for disease diagnosis. The work will be done in collaboration with an international team of structural biologists from the University of York (G. J. Davies) and chemical biologists from the University of Leiden (H. S. Overkleeft), with whom the group has established a fruitful collaboration. Computer resources will be provided by the Institute of Theoretical and Computational Chemistry (in-house research cluster) and the Barcelona Supercomputing Center.

References

M. K. Bilyard et al. Nature 2018, 563, 235-240.

Iglesias-Fernández et al. Nat. Chem. Biol. 2017, 13, 874–881.

T. J. M. Beenakker et al. J. Am. Chem. Soc. 2017, 139, 6534–6537.

A. Ardèvol, C. Rovira. J. Am. Chem. Soc. 2015, 137, 7528-7547.

G. J. Davies et al. Acc. Chem. Res. 2012, 45, 308–316.

A. Ardèvol, C. Rovira. Angew. Chem. Int. Ed. 2011, 50, 10897-10901.

OTHER RELEVANT WEBSITES

web page of the group leader at ICREA

https://www.icrea.cat/Web/ScientificStaff/carme-rovira–virgili-411