Berlin 2024 – scientific programme

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BP: Fachverband Biologische Physik

BP 21: Poster IIIb

BP 21.26: Poster

Wednesday, March 20, 2024, 11:00–14:30, Poster C

AlphaFold-driven modeling of cytochrome bd-I: A structural approach to antibiotic design — •Noah Rickermann, Jonathan Hungerland, and Ilia A. Solov'yov — University Oldenburg, Department of Physics, Carl-von-Ossietzky-Str. 9-11, 26129 Oldenburg, Germany

In the pursuit of novel antibiotics, targeting proteins involved in the metabolic pathways of pathogens has emerged as a promising strategy. The terminal oxidase cytochrome bd-I, found exclusively in bacteria (e.g. E. Coli or M. tuberculosis), serves as a promising target for antibiotics. However, incomplete structural data due to limitations of electron microscopy hinders a comprehensive understanding of the protein's function. This study introduces a computational model of the cytochrome bd-I complex, reconstructed using the AlphaFold protein structure prediction program, in combination with experimental information for placement of the prosthetic groups. Model validation incorporated the mutation study of Mogi et al. [1], who examined substrate binding properties in cytochrome bd-I. To assess the accuracy of the derived protein model free energy perturbation simulations were employed. Additionally, efforts were carried out to identify potential inhibitors for Cytochrome bd-I, yielding promising drug candidates in the early stages of the investigation [2-3].

[1] Mogi et al. Biochem. 45.25 (2006) [2] Jacobsen et al. "Introducing the Automated Ligand Searcher". J. Chem. Inf. Model. (2023) [3] Korol et al. "Introducing VIKING: A novel misc platform for multiscale modeling". ACS Omega 5.2 (2020)

Keywords: AlphaFold; Drug Development; Cytochrome; E. Coli; Free energy perturbation