An antiparallel beta-sheet and a beta-turn characterize the structure of antiviral HIV-1 peptide T140, as revealed by 2D NMR and MD Simulations.

The polyphemusins present in the hemocytes of the horsechoe crab and their structurally modified analogs have been shown to exhibit activity against HIV-1. Among the many variants, T22 ([Tyr(5,12), Lys(7)]-polyphemusin II), and its shorter and more potent analog, T140 [Arg(1)-Arg-2-Nal-Cys-Tyr(5)-Arg-Lys-D-Lys-Pro-Tyr(10)-Arg-Cit-Cys-Arg(14)] (Polyphemusin II-derived peptide), affect the HIV-cell fusion process and inhibit the T-cell line-tropic (T-tropic) HIV-1 infection. Conformational studies of polyphemusin II derived peptide have been carried out by (1)H and (13)C 2D-NMR and MD simulations in water and HFA (40%). The NMR parameters of chemical shift, temperature coefficients of the NH chemical shifts, (3)JNHalpha coupling constants and the pattern of nOe's were used to deduce the structural characteristics. Solution structures were generated using dihedral and distance restraints by MD simulations. The structures are characterized by a dominant family possessing an anti-parallel beta-pleated sheet that is constrained by the disulphide bridge between Cys4 and Cys13. The two strands of the beta-sheet are joined by a Type II' beta-turn spanning the residues Lys(7)-D-Lys(8)-Pro(9)-Tyr(10). This conformation is present in both water and HFA. The only difference in the two structures is that the beta-strands are more cohesive in HFA being firmly held by H-bonds. The solution structures generated from MD simulations were refined by MARDIGRAS to R-factors of 0.44 and 0.57 in water and HFA respectively. The conformation deduced for T140 is very similar to that reported for T22 and is thought to be associated with their anti HIV activity.