De Novo Design and Computational Validation of a High-Affinity Peptide Inhibitor Targeting the HPV E1-E2 Interface

The oncogenic progression of high-risk Human Papillomavirus (HPV) strains relies fundamentally on the cooperative interaction between the E1 replicative helicase and the E2 origin-binding protein to initiate viral DNA amplification. Disrupting this essential protein-protein interaction presents a highly promising, yet clinically unrealized, therapeutic paradigm for treating established HPV infections prior to malignant transformation. This research presents a comprehensive computational pipeline for evaluating and screening de novo generated peptide inhibitors. We utilize the HPV E1-E2 protein interface as a proof of concept, specifically targeting a highly conserved arginine triad located on the solvent-exposed surface of the E1 helicase. Utilizing the AlphaProteo generative model for sequence discovery and AlphaFold 3 for complex structural prediction, a library of candidate binders was generated and subsequently subjected to dual-scale Molecular Dynamics simulations and thermodynamic validation utilizing GROMACS. The results establish Binder 8 as the lead candidate, yielding a predicted binding free energy (-59.1 +/- 0.7 kcal/mol) that indicates a significantly stronger theoretical affinity than the native E1-E2 baseline. Energy decomposition confirms that Binder 8 binds the E1 interface via precise interactions involving the arginine triad. Furthermore, deep-learning-based physicochemical profiling utilizing CSM-Toxin and AlgPred 2.0 confirms that Binder 8 possesses an optimal safety profile, exhibiting zero predicted toxicity and non-allergenic properties. Protein sequence alignment confirms the evolutionary conservation of the targeted arginine triad across the vast majority of oncogenic Alpha-papillomavirus genotypes, highlighting Binder 8 as a viable promising candidate scaffold for broad-spectrum antiviral development. The study demonstrates a computational solution for E1-E2 disruption, setting the stage for future in vitro validation via Bio-layer interferometry to confirm physical inhibition.

Fletcher, S., Biswas-Fiss, E. E., Biswas, S. B.

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