Methionine Matters: Comparative Dynamic Insights Into Viral Inhibition of Host RNA Export via Rae1-Nup98

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.