Role of RNA Guanine Quadruplexes in Favoring the Dimerization of SARS Unique Domain in Coronaviruses

Cécilia Hognon; Tom Miclot; Cristina Garcia Iriepa; Antonio Francés-Monerris; Stephanie Grandemange; Alessio Terenzi; Marco Marazzi; Giampaolo Barone; Antonio Monari

To further examine the conformational space spanned by the G4/SUD complex, and in particular the role of the RNA in favoring the dimerization and the structure of the interface, we resorted to enhanced sampling MD simulations to obtain the 2D free energy profile along two relevant collective variables: first, the distance between G4 and SUD, and second, the separation between the two SUD subdomains. To further examine the conformational space spanned by the G4/SUD complex, and in particular the role of the RNA in favoring the dimerization and the structure of the interface, we resorted to enhanced sampling MD simulations to obtain the 2D free energy profile along two relevant collective variables: first, the distance between G4 and SUD, and second, the separation between the two SUD subdomains. The PMF is reported in Figure 5 together with representative snapshots along the reaction coordinates. A slightly less stable and extended region is also observed around the principal minimum having a stabilization free energy of about 6 kcal/mol and corresponding to the sliding of G4 slides in the monomer conformation ( Figure 5c ). The rest of the free energy surface appears instead rather flat, accounting for the possibility to observe important conformational movements, basically destroying the SUD subdomain interface (Figure 5d ), that are instead hampered by the dimer-like conformation of the RNA. The free energy map unambiguously shows that the dimer mode is the preferred one, offering a specific target that may help in the development of new efficient antiviral agents against coronaviruses.