Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Molecular Dynamics Simulations and MM/PBSA Analysis of Annocatacin B in ND1 Subunit of Human Mitochondrial Respiratory Complex I

Version 1 : Received: 1 May 2021 / Approved: 3 May 2021 / Online: 3 May 2021 (16:13:49 CEST)

A peer-reviewed article of this Preprint also exists.

Febres-Molina, C.; Aguilar-Pineda, J.A.; Gamero-Begazo, P.L.; Barazorda-Ccahuana, H.L.; Valencia, D.E.; Vera-López, K.J.; Davila-Del-Carpio, G.; Gómez, B. Structural and Energetic Affinity of Annocatacin B with ND1 Subunit of the Human Mitochondrial Respiratory Complex I as a Potential Inhibitor: An In Silico Comparison Study with the Known Inhibitor Rotenone. Polymers 2021, 13, 1840. Febres-Molina, C.; Aguilar-Pineda, J.A.; Gamero-Begazo, P.L.; Barazorda-Ccahuana, H.L.; Valencia, D.E.; Vera-López, K.J.; Davila-Del-Carpio, G.; Gómez, B. Structural and Energetic Affinity of Annocatacin B with ND1 Subunit of the Human Mitochondrial Respiratory Complex I as a Potential Inhibitor: An In Silico Comparison Study with the Known Inhibitor Rotenone. Polymers 2021, 13, 1840.

Journal reference: Polymers 2021, 13, 1840
DOI: 10.3390/polym13111840

Abstract

ND1 subunit possesses the majority of the inhibitor binding domain of the human MRC-I. This is an attractive target for the search for new inhibitors that seek mitochondrial dysfunction. It is known, from in vitro experiments, some metabolites from Annona muricata called acetogenins have important biological activities such as anticancer, antiparasitic, and insecticide. Previous studies propose an inhibitory activity of bovine MRC-I by bis-THF acetogenins such as annocatacin B, however, there are few studies on its inhibitory effect on human MRC-I. In this work, we evaluate the molecular and energetic affinity of the annocatacin B molecule with the human ND1 subunit in order to elucidate its potential capacity to be a good inhibitor of this subunit. For this purpose, QM optimizations, MD simulations and MM/PBSA analysis were performed. As a control to compare our outcomes, the molecule rotenone, which is a known MRC-I inhibitor, was chosen. Our results show that annocatacin B has a greater affinity for the ND1 structure, its size and folding were probably the main characteristics that contributed to stabilize the molecular complex. Furthermore, the MM/PBSA calculations showed a 35% stronger BFE compared to the rotenone complex. Detailed analysis of the BFE shows that the aliphatic chains of annocatacin B play a key role in molecular coupling by distributing favorable interactions throughout the major part of the ND1 structure. These results are consistent with experimental studies that mention that acetogenins may be good inhibitors of MRC-I.

Subject Areas

Annocatacin B; ND1 Subunit; Mitochondrial Respiratory Complex I; MRC-I; Molecular Dynamics Simulations; MD; Hirshfeld Charges; MM/PBSA

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