Synthetic peptide antigens corresponding to the entire third variable region V3, the principal neutralizing determinant of the human immunodeficiency virus (HIV) envelope glycoprotein of HIV‐1 subtype B (1), HIV‐2 subtype A (5), and HIV‐2 subtype B (7) were synthesized by solid‐phase peptide synthesis (Table 1). 1 and 5 were also prepared as their GlcNAc‐glycosylated forms at the natural N‐glycosylation site NXT (positions 6–8; peptides 4 and 6). Additionally, the proposed β‐turn region of 1 (GPGR; positions 15–18) was altered by introducing D‐Ala17 (2) and D‐Pro16 (3). All compounds have been studied by two‐dimensional NMR techniques. Interproton distances and 3JNH/Hα coupling constants derived from NMR data are used as restraints in distance geometry and ENSEMBLE‐Distance and angle‐bound driven dynamics calculations. The simulations led to disordered conformations except for a high propensity of a βII‐turn in the region GPXR (positions 15–18) in 1, 2, and 4. In 3 (G‐D‐ProGR, positions 15–18), a type βII‐turn was mainly found instead. For peptide 7, the consensus sequence of HIV‐2 subtype B, a type βrturn was also found although the primary structure (VSGL; positions 15–18) differs grossly from the HIV‐1 peptide 1. With the exception of 2, all βII turns were able to form a canonically opened β‐turn by a 180° rotation of φ(G17). Surprisingly, compounds 5 and 6 that are highly similar to 7 showed no βII type turn within MSGL (positions 15–18). They form a type βVIII‐turn across the tetrapeptide SGLV (positions 16–19) together with a non‐canonical turn conformation across LMSG (positions 14–17) leading to an S‐conformation. The reaction of the peptides with HIV‐positive sera from patients infected with different subtypes of HIV‐1 and HIV‐2 was tested in enzyme‐linked immunosorbent assays (ELISA reactions). No HIV‐2 sera reacted with peptide 1 and no HIV‐1 sera showed reactivity to peptide 5. We propose that certain amino acid exchanges within the V3 domain lead to altered conformations of the V3 loop resulting in antibodies that show altered binding properties to the peptide antigens used in the ELISA reactions.

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