Computational Investigation of Structural Interfaces of Protein Complexes with Short Linear Motifs.

Protein complexes with short linear motifs (SLiMs) are known to play important regulatory functions in eukaryotes. In this investigation, I have studied the structures deposited in PDB with SLiMs. The structures were grouped into three broad categories of protein-protein, protein-peptide, and the rest as others. Protein-peptide complexes were found to be most highly represented. The interfaces were evaluated for geometric features and conformational variables. It was observed that protein-protein and protein-peptide complexes show characteristic differences in residue pairings, which were quantified by evaluating normalized contact residue pairing frequencies. Interface residues adopt characteristic canonical residue conformations in the Ramachandran space, with a pronounced preference for positive ϕ conformations. It was observed that phosphorylated residues have an unusual propensity to adopt the positive ϕ conformations at the interface.

Molecular dynamics insights on the role ß-augmentation of the peptide N-terminus with binding site ß-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 â†’ Tyr374) with designed peptides provide insights into the mechanism of peptide binding at the protein interface. We establish that ß-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.