Rapid in silico Design of Potential Cyclic Peptide Binders Targeting Protein-Protein Interfaces.

Brianda L Santini,Martin Zacharias

doi:10.3389/fchem.2020.573259

Abstract

Rational design of specific inhibitors of protein-protein interactions is desirable for drug design to control cellular signal transduction but also for studying protein-protein interaction networks. We have developed a rapid computational approach to rationally design cyclic peptides that potentially bind at desired regions of the interface of protein-protein complexes. The methodology is based on comparing the protein backbone structure of short peptide segments (epitopes) at the protein-protein interface with a collection of cyclic peptide backbone structures. A cyclic peptide that matches the backbone structure of the segment is used as a template for a binder by adapting the amino acid side chains to the side chains found in the target complex. For a small library of cyclic peptides with known high resolution structures we found for the majority (~82%) of 154 protein-protein complexes at least one very well fitting match for a cyclic peptide template to a protein-protein interface segment. The majority of the constructed protein-cyclic peptide complexes was very stable during Molecular Dynamics simulations and showed an interaction energy score that was typically more favorable compared to interaction scores of typical peptide-protein complexes. Our cPEPmatch approach could be a promising approach for rapid suggestion of cyclic peptide binders that could be tested experimentally and further improved by chemical modification.

Highlights

Protein-protein interactions (PPIs) serve as the basis for most biological processes, they play key roles in intercellular communication, cell-to-cell signaling, metabolic and developmental control, and programmed cell death (Fontaine et al, 2015)
The workflow of the cPEPmatch that we propose in this work is based on the idea that the shape of the backbone structure of the PPI interfaces plays a key role in the binding interaction between these short motifs (Kallen et al, 1998)
Identification of cyclic peptides that bind to the interface region of protein-protein complexes may provide a promising route for modulating PPIs (Qian et al, 2017)

Summary

Introduction

Protein-protein interactions (PPIs) serve as the basis for most biological processes, they play key roles in intercellular communication, cell-to-cell signaling, metabolic and developmental control, and programmed cell death (Fontaine et al, 2015). Abnormal regulation of PPIs results in many human diseases such as cancers, immune disorders, and neurodegenerative diseases Modulating these aberrant interactions is of clinical relevance, targeting PPIs may be challenging because of the intrinsic properties of protein–protein interfaces (Ryan and Matthews, 2005; Villoutreix et al, 2014). Been made in targeting protein-protein interactions (PPI) by realizing that not all Cyclopeptide Design for Targeting PPI the surface area of a PPI contributes to the strength of the interaction between the protein partners (Keskin et al, 2005; Wells and McClendon, 2007; Arkin et al, 2014) Their binding is mediated by strong packing or electrostatic interactions where only a few neighboring amino acids are crucial for binding and recognition. Targeting protein–protein interaction hot spots still tends to require complex drug molecules (Fry, 2006)

Methods

Results

Conclusion