Designing Analogues of Mini Atrial Natriuretic Peptide Based on Structural Analysis by NMR and Restrained Molecular Dynamics

Analogues of mini atrial natriuretic peptide (miniANP) that provide conformational properties related to biological activity were designed on the basis of the structure revealed by NMR and restrained molecular dynamics (rMD) simulation, and an analogue with a high level of biological activity was successfully obtained. MiniANP is a cyclic pentadecapeptide analogue of atrial natriuretic polypeptide (ANP). The conformation of miniANP analyzed by NMR and rMD simulation indicated that positive φ angles are preferred for Gly5 and Gly6, which is typical for d-amino acids. On the basis of the structural information, [d-Ala5]miniANP, [d-Ala6]miniANP, and [d-Ala5 d-Ala6]miniANP were synthesized. The biological activity of [d-Ala5]miniANP was stronger than that of miniANP, confirming that Gly5 of miniANP takes a positive φ angle on binding to the receptor. Conformational analysis of these analogue peptides by NMR suggested that a turnlike conformation at residues 6−9 and a proximate pair formed by side chains of Phe4 and Ile11 are important for the biological activity.