T‐705‐modified ssRNA in complex with Lassa virus nucleoprotein exhibits nucleotide splaying and increased water influx into the RNA‐binding pocket

Abstract

Lassa virus infection is clinically characterized by multiorgan failure in humans. Without an FDA‐approved vaccine, ribavirin is the frontline drug for the treatment but with attendant toxicities. 6‐Fluoro‐3‐hydroxy‐2‐pyrazinecarboxamide (T‐705) is an emerging alternative drug with proven anti‐Lassa virus activity in experimental model. One of the mechanisms of action is its incorporation into nascent single‐strand RNA (ssRNA) which forms complex with Lassa nucleoprotein (LASV‐NP). Here, using molecular dynamics simulation, the structural and electrostatics changes associated with LASV‐NP‐ssRNA complex have been studied when none, one, or four of its bases has been substituted with T‐705. The results demonstrated that glycosidic torsion angle χ (O4′‐C1′‐N1‐C2) rotated from high‐anti‐ (−110° and −60°) to the syn‐ conformation (+30) with increased T‐705 substitution. Similarly, increased T‐705 substitution resulted in increased splaying (55°–70°), loss of ssRNA‐LASV‐NP H‐bond interaction, increased water influx into the ssRNA‐binding pocket, and decreased electrostatic potentials of ssRNA pocket. Furthermore, strong positively correlated motion observed between α6 residues (aa: 128–145) and its contact ssRNA bases (5–7) is weakened in Apo biosystem and transitioned into anticorrelated motions in ssRNA‐bound LASV‐NP biosystem. Finally, LASV genome may become more accessible to cellular ribonuclease access with T‐705 incorporation due to loss of NP interaction.

Markov State Model of Lassa Virus Nucleoprotein Reveals Large Structural Changes during the Trimer to Monomer Transition

“…It was also found that the position of helix 6 in the open state is influenced by crystal contacts, and when NP is free in solution the helix 6 position may be closer to the RNA-binding pocket. This observation was also noted in another simulation study of Lassa NP (Omotuyi et al, 2019).…”

Inhibition of SARS-COV-2 Receptor-Binding domain/ACE2 by Bazedoxifene

“…During biosystem build-up, protein and ligand atoms were de ned by CHARMM36 all-atom additive force eld parameters, solvated in TIP3P explicit water model and neutralized with Na + /CL − at 0.15 M 17 . Details of biosystem setup using CHARMM-GUI have been previously published [18][19][20] .…”