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. 2024 Feb:590:109946.
doi: 10.1016/j.virol.2023.109946. Epub 2023 Dec 11.

Computational and AI-driven 3D structural analysis of human papillomavirus (HPV) oncoproteins E5, E6, and E7 reveal significant divergence of HPV E5 between low-risk and high-risk genotypes

Riley N Jones  1 , Sayuri Miyauchi  1 , Souvick Roy  1 , Nathalie Boutros  1 , Jyoti S Mayadev  1 , Loren K Mell  2 , Joseph A Califano  3 , Aldo Venuti  4 , Andrew B Sharabi  5
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Free article

Computational and AI-driven 3D structural analysis of human papillomavirus (HPV) oncoproteins E5, E6, and E7 reveal significant divergence of HPV E5 between low-risk and high-risk genotypes

Riley N Jones et al. Virology. 2024 Feb.
Free article

Abstract

There are over 220 identified genotypes of Human papillomavirus (HPV), and the HPV genome encodes 3 major oncogenes, E5, E6, and E7. Conservation and divergence in protein sequence and function between low-risk versus high-risk oncogenic HPV genotypes has not been fully characterized. Here, we used modern computational and structural folding algorithms to perform a comparative analysis of HPV E5, E6, and E7 between multiple low risk and high risk genotypes. We first identified significantly greater sequence divergence in E5 between low- and high-risk genotypes compared to E6 and E7. Next, we used AlphaFold to model the structure of papillomavirus proteins and complexes with high confidence, including some with no established consensus structure. We observed that HPV E5, but not E6 or E7, had a dramatically different 3D structure between low-risk and high-risk genotypes. To our knowledge, this is the first comparative analysis of HPV proteins using Alphafold artificial intelligence (AI) system. The marked differences in E5 sequence and structure in high-risk HPVs may contribute in important and underappreciated ways to the development of HPV-associated cancers.

Keywords: AI; Alphafold; Divergence; E5; E6; E7; HPV; Homology; Oncoprotein; Papillomavirus; Structural analysis.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This research was supported by discretionary and startup funds. A.B. Sharabi reports being a paid consultant/advisory board member for AstraZeneca, Primmune, Merck, and Jounce Therapeutics; reports receiving commercial research grants from Varian Medical Systems and Pfizer; reports being the scientific founder and has an equity interest in Toragen Inc. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict-of-interest policies. A. Venuti is a scientific advisory board member for Toragen Inc. J.S. Mayadev reports consulting for Varian Medical Systems, Merck, Primmune, and AstraZeneca.

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