The evolution of Momordica cyclic peptides

Area of Science:

• Evolutionary biology
• Biochemistry
• Molecular biology

Background:

• Cyclic proteins offer enhanced stability and function compared to acyclic forms.
• Momordica (Cucurbitaceae) seeds contain cyclic miniproteins (peptides) with potential biological activity.

Purpose of the Study:

• To investigate the evolutionary origins and mechanisms of cyclization in Momordica cyclic peptides.
• To identify key residues involved in the function and target binding of these peptides.
• To explore the potential of Momordica cyclic peptides in therapeutic applications.

Main Methods:

• Phylogenetic analysis of Momordica species and their cyclic peptide precursors.
• Identification of mutations associated with head-to-tail cyclization.
• Molecular dynamics simulations of cyclic peptides complexed with trypsin.
• Evolutionary selection analysis.

Main Results:

• Momordica cyclic peptides evolved from an African ancestor approximately 19 million years ago.
• Head-to-tail cyclization arose from mutations in acyclic precursor sequences following gene expansion events.
• Evolutionary analysis identified specific residues under selection, crucial for trypsin inhibitory function.
• Molecular dynamics revealed site-specific interactions between peptides and trypsin.

Conclusions:

• The evolution of Momordica cyclic peptides involves specific mutations enabling cyclization and conferring potent trypsin inhibitory activity.
• These findings provide a foundation for studying cyclic peptide biosynthesis and developing new therapeutic agents targeting serine proteases.
• Momordica cyclic peptides represent a promising source for novel drug discovery against diseases involving related proteases.