Methionine matters: a common mechanism of viral inhibition of host defense identified via AI-assisted molecular dynamics.

Diverse groups of viruses infecting higher eukaryotes inhibit mRNA export via physical blockage of the Rae1-Nup98 complex within the host cell's nucleopore. This is thought to most often involve the critical placement of hydrophilic flanked single methionine residues along polypeptide extensions that reach into the nucleopore. However, it is unknown how this presumably conserved mechanism might function across diverse viral taxa. Here we employ a comparative molecular dynamics (MD) approach comparing motions of wild-type and mutant viral proteins in Rae-Nup98 bound vs. unbound states. Our comparisons of MD simulations are enhanced by kernel-based denoising allowing the isolation of non-random functional dynamics from random thermal noise. We demonstrate that despite large structural differences, three evolutionarily distinct viral systems (i.e. VSV M protein, SARS-CoV2 ORF 6, and KSHV ORF 10) share nearly identical single methionine-dependent functional dynamics related to the host cell inhibition of nuclear transport. This finding strongly supports a convergently-evolved common functional mechanism across viruses involving specific structural placement of non-polar residues like methionine and potentially providing a common therapeutic target for broad spectrum anti-viral treatment.