March 13, 2026Open Access

A Computational Structural Analysis of Host Insertions in the Polyproline Region of the Hepatitis E Virus pORF1 Polyprotein

Key Result

Host genome insertions in the polyproline region of hepatitis E virus pORF1 increased its replication rate by enhancing hydrogen bonding, improving stability of the MetY domain.

Key Points

This study aims to understand how host genome insertions in the polyproline region of the hepatitis E virus pORF1 polyprotein affect its replication rate.
Characterized 25 strains of hepatitis E virus with genome insertions using computational modeling.
Conducted molecular dynamics simulations to explore structural variations in the pORF1 polyprotein.
Analyzed the stability of pORF1 and its interactions with other viral domains.
Strains with insertions showed an increased replication rate compared to wild-type strains.
Insertions did not alter the structural organization or intrinsically disordered nature of the polyproline region.
Increased hydrogen bonds between the polyproline region and the MetY domain and RdRp were observed in insertion strains.
The MetY domain's stability was higher in strains with host insertions than in wild-type strains.

Structured PICO

Population

In silico modeling of pORF1 across 25 strains of Hepatitis E virus

Intervention

Host genome insertions within the polyproline region (PPR) of the pORF1 polyprotein

Comparator

Wild-type (WT) strains

Outcome

Structural variations and potential mechanisms underlying increased replication rate (e.g., hydrogen bonds, stability)

Host insertions in the Hepatitis E virus pORF1 polyprotein may increase replication rates by forming additional hydrogen bonds that position the MetY domain and RdRp closer together.

Main Result

Absolute Event Rate: 0% vs 0%

Abstract

Hepatitis E virus, a single-stranded positive-sense RNA virus, is the causative agent of acute viral hepatitis in humans and can lead to chronic infection in immunocompromised individuals. In this setting, strains containing host genome insertions within the polyproline region (PPR) of the pORF1 polyprotein were characterized and shown to display an increased replication rate across all systems. Using in silico modeling of pORF1 across 25 strains, combined with molecular dynamics (MD) simulations, we explored the structural variations caused by these insertions to investigate potential mechanisms underlying the increased replication rate compared to wild-type (WT) strains. Our results showed that the insertions neither induced structural organization within the PPR nor altered its intrinsically disordered nature. MD simulations further demonstrated that the overall stability of pORF1 remained unchanged in strains with insertions compared to WT strains. On the other hand, MD analyses revealed that strains with insertions exhibited an increased number of hydrogen bonds between the PPR and two other domains of pORF1: the MetY domain and the RNA-dependent RNA polymerase (RdRp). The stability of the MetY domain of the strains in the presence of host insertion events was higher than in the WT strains. These additional hydrogen bonds could position the MetY domain and the RdRp closer together, potentially promoting more efficient viral RNA synthesis. Validation of this hypothesis will require experimental structural studies, as well as computational modeling of the proposed dodecameric pORF1 structure.