Phi (Φ) and psi (Ψ) angles involved in malarial peptide bonds determine sterile protective immunity

Area of Science:

• Immunology
• Structural Biology
• Vaccine Development

Background:

• Modified human antigen-binding peptide (mHABP) interactions with HLA-DRβ1(*) molecules are key to immune responses.
• Conformation and sequence of mHABPs influence their binding to peptide binding regions (PBR) and subsequent immune response.
• Torsion angles (Φ and Ψ) play a critical role in the immunogenicity of mHABPs.

Purpose of the Study:

• To investigate the structural basis of highly immunogenic mHABPs interacting with HLA-DRβ1(*).
• To determine the role of Φ and Ψ torsion angles in inducing protective immunity against experimental malaria.
• To establish new principles for vaccine development based on mHABP conformational preferences.

Main Methods:

• Conformational analysis of mHABPs using (1)H-NMR.
• Superimposition of mHABP conformers onto HLA-DRβ1(*)-like Aotus monkey molecules.
• Measurement of Φ and Ψ angles and evaluation of H-bond formation.

Main Results:

• mHABPs interacting with HLA-DRβ1(*) exhibit restricted conformations compared to non-immunogenic ones.
• A specific propensity for a left-handed polyproline type II helix (PPII(L)) conformation was observed in immunogenic mHABPs.
• The measured Φ and Ψ angles and H-bond formations correlated with immune response induction.

Conclusions:

• Favorable mHABP conformations, particularly PPII(L)-like structures, are critical for high antibody titre production and sterile immunity against malaria.
• Amino acid sequence can be manipulated to favor these protective conformations.
• This study provides new rules for designing effective malaria vaccines.