Computational modeling of SARS-CoV-2 Nsp1 binding to human ribosomal 40S complex

Molecular docking and Targeted Molecular Dynamics Simulations were conducted to elucidate binding properties of SARS-CoV-2 nonstructural protein 1 (nspl) onto the human ribosomal 40S complex. Nspl serves as a host shutoff factor by blocking ribosome assembly on host mRNAs, thereby suppressing host gene expression. Recently, cryo-electron microscope structure of both 40S and 80S ribosome purified in the presence of SARS-CoV-2 nspl revealed the presence of the C-terminal region of nspl in the mRNA binding site of the 40S ribosome. This structure gives the first insight into the molecular mechanism of nspl-mediated suppression of host protein translation. In this study we have utilized the most recent emerging partial structures of nspl bound to 40S ribosome as the reference point of implementing a Targeted Molecular Dynamics Simulation of the entire nspl bound to the 40S complex. Our final bound structure of nspl exhibits the previously reported helix-turn-helix conformation of the C-terminal region of nspl and satisfies all the previously reported proximity restraints. Finally, we have established the interaction and stability of this final bound state of the full nspl and 40S. The observation that C-terminal region of nspl folds into a helix-turn-helix structure to occupy the mRNA binding site in the 40S ribosome enables further inquiry into the understanding of the entire nspl structure bound to the 40S ribosome to reveal relative positioning of the two termini when nspl is bound to ribosome.