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†
2022-03-16
Johannes C. B. Dietschreit, Beatriz von der Esch and Christian Ochsenfeld
Phys. Chem. Chem. Phys.24, 7723, 2022
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 via exponential averaging over AM pathways. Based on our previous study [von der Esch et al., J. Chem. Theory Comput., 2019, 15, 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 via an SN2-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.
Speaker: Prof. Dr. Thomas Carell
Ludwig-Maximilians-Universität München
Institut für Chemische Epigenetik (ICEM)
Department of Chemistry
Office:
Würmtalstrasse 201
81377 Munich
Germany
Mailing address:
Butenandtstr. 5 - 13
81377 Munich
Germany
Phone: +49 (0)89 2180-77750
Fax: +49 (0)89 2180-77756
Email: This email address is being protected from spambots. You need JavaScript enabled to view it.
Management: Dr. Nada Raddaoui
Institute for Chemical Epigenetics Munich (ICEM)
Office:
Würmtalstrasse 201, Building L, Room 03.004
81377 Munich
Germany
Mailing address:
Butenandtstr. 5 - 13
81377 Munich
Germany
Phone: +49 (0)89 2180-77755
Email: This email address is being protected from spambots. You need JavaScript enabled to view it.
Secretary: Birgit Carell
Institute for Chemical Epigenetics Munich (ICEM)
Office:
Würmtalstrasse 201, Building L, Room 00.007
81377 Munich
Germany
Mailing address:
Butenandtstr. 5 - 13
81377 Munich
Germany
Phone: +49 (0)89 2180-77751
Email: This email address is being protected from spambots. You need JavaScript enabled to view it.
website support: Martina Schuster
Prof. Dr. Lena Daumann
LMU Munich
Department of Chemistry
Butenandtstr. 5 - 13
House D, Room 3.075
81377 Munich, Germany
Phone: +49 89 2180 77486
This email address is being protected from spambots. You need JavaScript enabled to view it.
Dr. Sabine Schneider
LMU Munich
Institute for Chemical Epigenetics
Butenandtstr. 5 - 13
House L
81377 Munich, Germany
Phone: +49 89 2180 77716
This email address is being protected from spambots. You need JavaScript enabled to view it.
Dr. Martin Sumser (Coordinator)
LMU Munich
Institute for Chemical Epigenetics
Butenandtstr. 5 - 13
House L
81377 Munich, Germany
Phone: +49 89 2180 77765
This email address is being protected from spambots. You need JavaScript enabled to view it.
Contact IRTG 1309 related
Email: This email address is being protected from spambots. You need JavaScript enabled to view it.