A new dimerization interface in HCV NS5A

Hepatitis C virus RNA synthesis, driven by the polymerase NS5B, is regulated by its interaction with NS5A at the endoplasmic-reticulum membrane — studied in Dr. Stéphane Bressanelli’s team in collaboration with Prof. Volker Lohmann (Heidelberg University Hospital).

Modelling NS5A and NS5B together, I found a topology consistent with membrane insertion of the NS5A/NS5B dimer — NS5A’s amphipathic helix sitting at the membrane surface while its transmembrane helix crosses the bilayer — and, more surprisingly, a previously undescribed NS5A dimerization interface, which I called D2. With Gabriel Vanegas Arias, then an engineering-school intern, I ran molecular-dynamics simulations that supported the stability of this interface, while preliminary ITC and NMR data from our collaborators were consistent with the predicted dimer.

These models directly supported a successful ANRS PhD fellowship to determine the interface’s crystallographic structure. The dimerization site has since been validated experimentally.