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Conformational Heterogeneity of Pro-Pro Containing 23-Membered Ring Conopeptides by NMR

Pooja Dhurjad¹, Srinivas Reddy Dannarm¹, Khajapeer Shaik¹

¹Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana 500037, India.

|November 24, 2025

Summary

Conformational diversity in conopeptides Be828 and Li833 from Conus snails was studied. Li833 exhibits significant conformational heterogeneity due to consecutive prolines, unlike Be828, offering insights for peptide design.

Area of Science:

Biochemistry
Structural Biology
Peptide Chemistry

Background:

Conopeptides are venom peptides from Conus snails with diverse biological activities.
Contryphans, a subclass of conopeptides, exhibit unusual proline-rich sequences.
Understanding conopeptide conformation is crucial for drug design.

Purpose of the Study:

To investigate the conformational diversity of two contryphans, Be828 and Li833.
To explore the role of consecutive prolines in peptide conformation.
To elucidate the factors influencing conformational heterogeneity in 23-membered conopeptide rings.

Main Methods:

Nuclear Magnetic Resonance (NMR) spectroscopy to determine peptide structures.
Synthesis of analogues to study structure-activity relationships.
Analysis of secondary structures, including beta-turns.

Main Results:

Be828 adopts a single trans-trans conformation around proline residues.
Li833 exhibits four distinct conformers due to cis-trans isomerization around consecutive prolines.
Conformational heterogeneity in Li833 is influenced by disulfide loop constraints and specific residues (Y2, R3).
Be828 is stabilized by a type IV4 beta-turn, while Li833 predominantly adopts a type VIa1 beta-turn.

Conclusions:

Consecutive prolines introduce significant conformational flexibility in 23-membered conopeptide rings.
Disulfide loop constraints and flanking residues play a critical role in modulating peptide conformation.
This study provides insights into designing peptide-based ligands with tailored conformational properties.

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