posted on 2024-07-15, 14:16authored byHung Nguyen, Hoang Linh Nguyen, Mai Suan Li
Experimental evidence has established that SARS-CoV-2
NSP1 acts
as a factor that restricts cellular gene expression and impedes mRNA
translation within the ribosome’s 40S subunit. However, the
precise molecular mechanisms underlying this phenomenon have remained
elusive. To elucidate this issue, we employed a combination of all-atom
steered molecular dynamics and coarse-grained alchemical simulations
to explore the binding affinity of mRNA to the 40S ribosome, both
in the presence and absence of SARS-CoV-2 NSP1. Our investigations
revealed that the binding of SARS-CoV-2 NSP1 to the 40S ribosome leads
to a significant enhancement in the binding affinity of mRNA. This
observation, which aligns with experimental findings, strongly suggests
that SARS-CoV-2 NSP1 has the capability to inhibit mRNA translation.
Furthermore, we identified electrostatic interactions between mRNA
and the 40S ribosome as the primary driving force behind mRNA translation.
Notably, water molecules were found to play a pivotal role in stabilizing
the mRNA-40S ribosome complex, underscoring their significance in
this process. We successfully pinpointed the specific SARS-CoV-2 NSP1
residues that play a critical role in triggering the translation arrest.