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

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ID: 24345
2019
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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. This article is protected by copyright. All rights reserved.
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pasam2019molecularchemical Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Pasam, Bhargavi;Medicherla, Krishna Mohan;Rathore, Ravindranath Singh;Upadhyayula, Raghavender Surya;
Journal Chemical biology & drug design
Year 2019
DOI
10.1111/cbdd.13612
URL
Keywords Keywords not found

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