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.
Keywords: low-density lipoprotein receptor; molecular dynamics; proprotein convertase subtilisin/kexin 9; protein-peptide interactions; short linear motif.
© 2019 John Wiley & Sons A/S.