Molecular dynamics insights on the role β‐augmentation of the peptide N‐terminus with binding site β‐hairpin of proprotein convertase subtilisin/kexin 9

PCSK9, a member of the proprotein convertase family, is a key negative regulator of hepatic low‐density lipoprotein receptor (LDLR) concentrations in the blood plasma and is associated with the risk of coronary artery disease (CAD). Peptide inhibitors designed to block PCSK9‐LDLR interactions could reduce the risk of CAD. We present a study of the interaction of a PCSK9 bound peptide and its design through modification by phosphorylation using molecular dynamics simulations. Extensive explicit solvent simulations of PCSK9 and its mutant (Asp374 → Tyr374) with designed peptides provide insights into the mechanism of peptide binding at the protein interface. We establish that β‐augmentation is the key mechanism of peptide association with PCSK9. Position‐specific phosphorylation of threonine residues is observed to have noticeable effect in modulating protein–peptide association. This study provides a handle to explore and improve the design of peptides bound to PCSK9 by incorporating knowledge‐derived functional motifs into designing potent binders. The role of unstructured peptide terminus at the interface and the effect of β‐augmentation in association with PCSK9. The design with phosphorylated peptides mimics PCSK9‐LDLR interaction.