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Sequence to structure analysis of the ORF4 protein from Hepatitis E virus



Zoya Shafat1, Anwar Ahmed2, Mohammad K. Parvez3 & Shama Parveen1,*



1Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India; 2Centre of Excellence in Biotechnology Research, College of Science, King Saud University, Riyadh, Saudi Arabia; 3Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia;



*Corresponding author: Shama Parveen - Email: sparveen2@jmi.ac.in;  Zoya Shafat - zoya179695@st.jmi.ac.in; Anwar Ahmed - anahmed@ksu.edu.sa; Mohammad K. Parvez - mohkhalid@ksu.edu.sa


Article Type

Research Article



Received August 14, 2021; Revised September 21, 2021; Accepted September 21, 2021, Published September 30, 2021



Hepatitis E virus (HEV) is the main cause of acute hepatitis worldwide. HEV accounts for up to 30% mortality rate in pregnant women, with highest incidences reported for genotype 1 (G1) HEV. The contributing factors in adverse cases during pregnancy in women due to HEV infection is still debated. The mechanism underlying the pathogenesis of viral infection is attributed to different genomic component of HEV, i.e., open reading frames (ORFs): ORF1, ORF2, ORF3 and ORF4. Recently, ORF4 has been discovered in enhancing the replication of GI isolates of HEV through regulation of an IRES-like RNA element. However, its characterization through computational methodologies remains unexplored. In this novel study, we provide comprehensive overview of ORF4 proteinís genetic and molecular characteristics through analyzing its sequence and different structural levels. A total of three different datasets (Human, Rat and Ferret) of ORF4 genomes were built and comparatively analyzed. Several non-synonymous mutations in conjunction with higher entropy values were observed in rat and ferret datasets, however, limited variation was observed in human ORF4 genomes. Higher transition to tranversion ratio was observed in the ORF4 genomes. Studies have reported the association of intrinsic disordered proteins (IDP) with drug discovery due to its role in several signaling and regulatory processes through protein-protein interactions (PPIs). As PPIs are potent drug target sources, thus the ORF4 protein was explored by analyzing its polypeptide structure in order to shed light on its intrinsic disorder. Pressures that lead towards preponderance of disordered-promoting amino acid residues shaped the evolution of ORF4. The intrinsic disorder propensity analysis revealed ORF4 protein (Human) as a highly disordered protein (IDP). Predominance of coils and lack of secondary structure further substantiated our findings suggesting its involvement in binding to ligand molecules. Thus, ORF4 contributes to cellular signaling processes through protein-protein interactions, as IDPs are targets for regulation to accelerate the process of drug designing strategies against HEV infections.



Hepatitis E virus (HEV), open-reading frame 4 (ORF4), mutational analysis, entropy analysis, gene selection pressure, nucleotide diversity, transition/transversion ratio, structural analysis, intrinsic disordered proteins (IDPs), drug target



Shafat et al. Bioinformation 17(9): 818-828 (2021)


Edited by

P Kangueane






Biomedical Informatics



This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.