New catalytic mechanisms in carbohydrate-active enzymes (CAZymes) unveiled by computer simulation

Professor Carme Rovira
Department of Inorganic and Organic Chemistry & Institute of Computational and Theoretical Chemistry (IQTCUB), University of Barcelona

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Abstract:

Carbohydrate-active enzymes (CAZymes), such as glycoside hydrolases and glycosyltransferases, constitute the main machinery for the degradation, synthesis and modification of carbohydrates in nature. They have a myriad of industrial and biotechnological applications, ranging from biofuel production to biotherapeutics. Understanding how carbohydrate are processed by CAZymes, identifying the catalytic residues, the role of enzyme conformational transitions and the conformation of the substrate at the transition state of the chemical reaction, can guide inhibitor design.  Using state-of-art simulation techniques such as ab initio quantum mechanics/molecular mechanics (QM/MM) and metadynamics [1-3] we have contributed to answer these questions, providing an atomistic view of enzyme action. In this talk I will describe some of the CAZyme mechanisms that we have recently investigated [4-6], in a collaborative work with research groups of structural and chemical biology.

[1] Laio, A.; Parrinello, M. Proc. Nat. Acad. Sci. U.S.A. 2002, 99, 12562-12566.

[2] Ardèvol, A.; Rovira, C. J. Am. Chem. Soc. 2015, 137, 7528-7547.

[3] J. Coines, L. Raich, C. Rovira. Curr. Opin. Chem. Biol. 2019, 53, 183-191.

[4]  L. F. Sobala, G. Speciale, S. Zhu, L. Raich, N. Sannikova, A. J. Thompson, Z. Hakki, D. Lu, Y. Zhang, S. S. K. Abadi, A. R. Lewis, V. Rojas-Cervellera, G. Bernardo-Seisdedos, O. Millet, J. Jiménez-Barbero, A. J. Bennet, M. Sollogoub, C. Rovira, G. J Davies, S. J. Williams, ACS Cent. Sci. 2020, 6, 760–770.

[5] M. K. Bilyard, H. Bailey, L. Raich, M. Gafitescu, T. Machida, J. Iglesias-Fernández, S. S. Lee, C. D. Spicer, C. Rovira, W. W. Yue, B. G. Davis, Nature 2018, 563, 235–240.

[6] M. A. B. Morais, J. Coines, M. N. Domingues, R. A. S. Pirolla, C. C. C. Tonoli, C. R. Santos, J. B. L. Correa, F. C. Gozzo, C. Rovira, M. T. Murakami. Nat. Commun. 2021, 12, 367.