Lab researchers study the HIV-1 maturation process in the millisecond regime

Maturation of HIV-1 particles encompasses a complex morphological transformation of Gag
via an orchestrated series of proteolytic cleavage events. A longstanding question concerns
the structure of the C-terminal region of CA and the peptide SP1 (CA–SP1), which represents
an intermediate during maturation of the HIV-1 virus. Employing enhanced sampling techniques in the Anton2 super computer researchers were able to observe the milisecond dynamics of the so-called SP1 domain. By integrating NMR, cryo-EM, and
molecular dynamics simulations, we show that SP1 acts as a maturation switch. In particular, we show that the SP1 peptide
exists in a dynamic helix–coil equilibrium, and that the addition of the maturation inhibitors
causes stabilization of a helical form of SP1.  Moreover, the
maturation-arresting SP1 mutation T8I also induces helical structure in SP1 and further global
dynamical and conformational changes in CA. Overall, our results show that dynamics of CA
and SP1 are critical for orderly HIV-1 maturation and that small molecules can inhibit maturation by perturbing molecular motions.  Results are published in the journal Nature Communications.