Abstract

Over time, viruses have evolved a myriad of mechanisms to gain an advantage in the virus-host battle, such as inhibiting host mRNA export through RNA Export Factor 1 (Rae1) and Nucleoporin 98 (Nup98). This strategy employed by the Vesicular Stomatitis Virus (VSV) M protein, Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) ORF10, and SARS-CoV-1/2 ORF6 disrupts antiviral production. Despite their evolutionary distance, these viral proteins share a key methionine flanked by acidic residues that competitively bind to the ssRNA binding pocket of Rae1. The VSV mutant, R1, carries an M51R mutation that disrupts viral inhibition and restores host gene export— a pattern observed in M→R mutants of SARS-CoV-1/2 ORF6 and KSHV ORF10. The underlying reasons for the methionine's critical role in the inhibition and restoration of host gene export remain unclear. Through comparative molecular dynamics using ATOMDANCE, we aim to investigate the mechanistic basis of these effects. Through computational mutagenesis, we simulated the effects of an M→R mutation and viral binding using comparative molecular dynamics. Our results revealed methionine binding stabilizes the complex, while mutations amplify coordinated motion, destabilizing interactions and decreasing competition for host ssRNA. These findings highlight a shared viral mechanism and lay the groundwork for future therapeutic strategies.

Library of Congress Subject Headings

Molecular dynamics; Messenger RNA; Methionine; Virus-induced immunosuppression

Publication Date

5-1-2025

Document Type

Thesis

Student Type

Graduate

Degree Name

Bioinformatics (MS)

College

College of Science

Advisor

Maureen Ferran

Advisor/Committee Member

Gregory Babbitt

Advisor/Committee Member

Julie Thomas

Campus

RIT – Main Campus

Plan Codes

BIOINFO-MS

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