Exponential averaging versus umbrella sampling for computing the QM/MM free energy barrier of the initial step of the desuccinylation reaction catalyzed by sirtuin 5

• Published in: Physical chemistry chemical physics : PCCP Vol. 24; no. 13; pp. 7723 - 7731
• Main Authors: Dietschreit, Johannes C B, von der Esch, Beatriz, Ochsenfeld, Christian
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 30.03.2022
• Subjects: Adiabatic flow; Catalysis; Chemical reactions; Energy; Free energy; Humans; Machine Learning; Mapping; Potential energy; Quantum Theory; Reaction mechanisms; Sampling; Sirtuins - metabolism
• ISSN: 1463-9076; 1463-9084
• DOI: 10.1039/d1cp05007a

The computational characterization of enzymatic reactions poses a great challenge which arises from the high dimensional and often rough potential energy surfaces commonly explored by static QM/MM methods such as adiabatic mapping (AM). The present study highlights the difficulties in estimating free energy barriers exponential averaging over AM pathways. Based on our previous study [von der Esch , , 2019, , 6660-6667], where we analyzed the first reaction step of the desuccinylation reaction catalyzed by human sirtuin 5 (SIRT5) by means of QM/MM adiabatic mapping and machine learning, we use, here, umbrella sampling to compute the free energy profile of the initial reaction step. The computational investigations show that the initial step of the desuccinylation reaction proceeds an S 2-type reaction mechanism in SIRT5, suggesting that the first step of the deacylation reactions catalyzed by sirtuins is highly conserved. In addition, the direct comparison of the extrapolated free energy barrier from minimal energy paths and the computed free energy path from umbrella sampling further underlines the importance of extensive sampling.