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

Abstract：

: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.

journal_name

Chem Biol Drug Des

journal_title

Chemical biology & drug design

authors

Pasam B,Medicherla KM,Rathore RS,Upadhyayula RS

doi

10.1111/cbdd.13612

subject

Has Abstract

pub_date

2019-12-01 00:00:00

pages

2073-2083

issue

6

eissn

1747-0277

issn

1747-0285

journal_volume

94

pub_type

杂志文章

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