Reading time: ~2 min · Part of the free certification in peptide science
Biological activity emerges from conformation, which is described in hierarchical levels:
- Primary: linear sequence. The master information.
- Secondary: alpha helices and beta sheets stabilized by backbone hydrogen bonds.
- Tertiary: overall shape, stabilized by disulfide bridges (Cys-Cys), hydrophobic interactions and ionic bonds.
- Quaternary: assembly of several chains (uncommon in short peptides).
Structure-activity relationship (SAR)
SAR is the framework that connects structural changes with changes in activity, and it is the basis of analog design. Key principles:
- Pharmacophore: the subset of residues and groups essential for receptor recognition. The rest tolerates changes; altering the pharmacophore abolishes activity.
- Conservative vs. non-conservative substitutions: replacing Leu with Ile (both hydrophobic) usually preserves function; replacing Leu with Asp (charged) usually alters it.
- Stereochemistry: introducing a D-amino acid or methylating a nitrogen alters recognition by proteases and sometimes by the receptor itself.
- Cyclization: restricts conformation and increases affinity and stability.
A single substitution can transform the molecule: turn a ligand with a half-life of minutes into a drug with a half-life of days, or an agonist into an antagonist. In peptides, the sequence is not a detail: it is the molecule.
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