DeProtCa Project

Enzymes, one of the most efficient and environmentally friendly catalysts, have attracted large attention from researchers during the last years due to the possibility of catalyzing new-to-nature chemical processes. For this purpose, hybrid molecular systems can be created that combine the broad reaction scope of synthetic catalysts with the exceptional catalytic performance, selectivity, and mild reaction conditions offered by protein scaffolds. Thus, many now recognize progress in enzyme design is a crucial stride toward transitioning to a sustainable economy.

Project Leader: Dr. Katarzyna Świderek

Although significant work has been done in developing computational and experimental techniques allowing for protein modifications, the variety of designed artificial enzymes is still minor, mostly due to limited knowledge about the origin of their catalytical power. This scarcity is a serious obstacle limiting new strategy performance. Computational chemistry tools, because they can explore chemical reactions at the molecular level, provide key insights into details that are impossible to be determined by measurements in a wet lab. Therefore, we propose to study several independent cases of artificial enzymes, such as those already designed and optimized experimentally, to shed more light on the role of the introduced modification along the way of their improvement. A variety of multiscale methods, mainly based on molecular dynamics (MD) simulations with QM/MM potentials, will be applied to explore chemical transformations occurring in the active sites of the proteins, and analytical tools will be used to explore the role of protein electrostatic fields and conformational rearrangements directly on catalysis. Our main objective is to determine key physical or chemical properties responsible for catalytic improvement and try to quantify them. The long-term goal would be to use the identified features and apply them in the design of enzymes with new functions.

Just Published:

L. Casalino, C. A. Ramos-Guzmán, R. E. Amaro*, C. Simmerling*, A. Lodola*, A. J. Mulholland*, K. Świderek*, V. Moliner* "A Reflection on the Use of Molecular Simulation to Respond to SARS-CoV-2 Pandemic Threats" J. Phys. Chem. Lett. 16, 3249–3263 (2025) DOI:10.1021/acs.jpclett.4c03654

K. Świderek, J. Bertran, K. Zinovjev, I. Tuñón, V. Moliner "Advances in the Simulations of Enzyme Reactivity in the Dawn of the Artificial Intelligence Age" WIREs Computational Molecular Science 15, e70003 (2025) DOI:10.1002/wcms.70003

S. Ferrer, V. Moliner, K. Świderek* "Electrostatic Preorganization in Three Distinct Heterogeneous Proteasome β-Subunits" ACS Catal. 14, 15237 (2024) DOI:10.1021/acscatal.4c04964

L. Zhang, L. Calvo-Barreiro, V. de Sousa Batista, K. Świderek,* M. T. Gabr* "Discovery of ICOS-Targeted Small Molecules Using Affinity Selection Mass Spectrometry Screening" ChemMedChem. e202400545 (2024) DOI:10.1002/cmdc.202400545

L. Williams, I.M. Taily, L Hatton, A.A. Berezin, Y.L. Wu, V. Moliner, K. Świderek*, Y. Tsai*, L.Y.P Luk* "Secondary Amine Catalysis in Enzyme Design: Broadening Protein Template Diversity through Genetic Code Expansion" Angew. Chemie Int. Ed. e202403098 (2024) DOI:10.1002/ange.202403098

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Research Relevant to the Project:

S. Ferrer, V. Moliner, K. Świderek "Electrostatic Preorganization in Three Distinct Heterogeneous Proteasome β-Subunits" ACS Catal. 14, 15237 (2024) DOI:10.1021/acscatal.4c04964

L. Williams, I.M. Taily, L Hatton, A.A. Berezin, Y.L. Wu, V. Moliner, K. Świderek, Y. Tsai, L.Y.P Luk "Secondary Amine Catalysis in Enzyme Design: Broadening Protein Template Diversity through Genetic Code Expansion" Angew. Chemie Int. Ed. e202403098 (2024) DOI:10.1002/ange.202403098

K. Świderek, S. Velasco-Lozano, M. À. Galmés, I. Olazabal, H. Sardon, F. López-Gallego, V. Moliner "Mechanistic studies of a lipase unveil effect of pH on hydrolysis products of small PET modules" Nat. Commun. 14:3556. (2023) doi: 10.1038/s41467-023-39201-1

N. Serrano-Aparicio, V.Moliner, K. Świderek "On the Origin of the Different Reversible Characters of Salinosporamide A and Homosalinosporamide A in the Covalent Inhibition of the Human 20S Proteasome" ACS Catal. 11, 11806–11819, (2021) doi:10.1021/acscatal.1c02614

M. À. Galmés, A. R. Nodling, K. He, L. Y. P. Luk, K. Świderek, V. Moliner "Computational design of an amidase by combining the best electrostatic features of two promiscuous hydrolases" Chem. Sci. 13, 4779-4787 (2022) doi:10.1039/d2sc00778a

A. Krzemińska, V. Moliner, K. Świderek "Dynamic and Electrostatic Effects on the Reaction Catalyzed by HIV-1 Protease." J. Am. Chem. Soc. 138, 16283–16298 (2016) DOI: 10.1021/jacs.6b06856