Buried polar interactions and conformational stability in the simian immunodeficiency virus (SIV) gp41 core

For human (HIV) and simian (SIV) immunodeficiency viruses, the gp41 envelop e protein undergoes a receptor-activated conformational change from a labil e native structure to an energetically more stable fusogenic conformation, which then mediates viral-cell membrane fusion. The core structure of fusio n-active gp41 is a six-helix bundle in which three antiparallel carboxyl-te rminal helices are packed against an amino-terminal trimeric coiled coil. H ere we show that a recombinant model of the SN gp41 core? designated N36(L6 )C34, forms an alpha-helical trimer that exhibits a cooperative two-state f olding-unfolding transition. We investigate the importance of buried polar interactions in determining the overall fold of the gp41 core. We have repl aced each of four polar amino acids at the heptad a and d positions of the coiled coil in N36(L6)C34 with a representative hydrophobic amino acid, iso leucine. The Q565I, T582I, and T586I variants form six-helix bundle structu res that are significantly mole stable than that of the wild-type peptide, whereas the Q575I variant misfolds into an insoluble aggregate under physio logical conditions. Thus, the buried polar residues within the amino-termin al heptad repeat are important determinants of the structural specificity a nd stability of the gp41 core. We suggest that these conserved buried polar interactions play a role in governing the conformational state of the gp41 molecule.