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Discovery of novel helix binding sites at protein-protein interfaces.

ABSTRACT: Protein-protein interactions (PPIs) play a key role in numerous biological processes. Many efforts have been undertaken to develop PPI modulators for therapeutic applications; however, to date, most of the peptide binders designed to target PPIs are derived from native binding helices or using the native helix binding site, which has limited the applications of protein-protein interface binding peptide design. Here, we developed a general computational algorithm, HPer (Helix Positioner), that locates single-helix binding sites at protein-protein interfaces based on the structure of protein targets. HPer performed well on known single-helix-mediated PPIs and recaptured the key interactions and hot-spot residues of native helical binders. We also screened non-helical-mediated PPIs in the PDBbind database and identified 17 PPIs that were suitable for helical peptide binding, and the helical binding sites in these PPIs were also predicted for designing novel peptide ligands. The L2 domain of EGFR, which was the top ranked, was selected as an example to show the protocol and results of designing novel helical peptide ligands on the searched binding site. The binding stability of the designed sequences were further investigated using molecular dynamics simulations.

SUBMITTER: Yang W

PROVIDER: S-EPMC6872852 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Discovery of novel helix binding sites at protein-protein interfaces.

Yang Wei W Sun Xiangyu X Zhang Changsheng C Lai Luhua L

Computational and structural biotechnology journal 20191111

Protein-protein interactions (PPIs) play a key role in numerous biological processes. Many efforts have been undertaken to develop PPI modulators for therapeutic applications; however, to date, most of the peptide binders designed to target PPIs are derived from native binding helices or using the native helix binding site, which has limited the applications of protein-protein interface binding peptide design. Here, we developed a general computational algorithm, HPer (Helix Positioner), that lo ...[more]

PMID: 31768230

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Project description:Many protein-protein interactions (PPIs) are compelling targets for drug discovery, and in a number of cases can be disrupted by small molecules. The main goal of this study is to examine the mechanism of binding site formation in the interface region of proteins that are PPI targets by comparing ligand-free and ligand-bound structures. To avoid any potential bias, we focus on ensembles of ligand-free protein conformations obtained by nuclear magnetic resonance (NMR) techniques and deposited in the Protein Data Bank, rather than on ensembles specifically generated for this study. The measures used for structure comparison are based on detecting binding hot spots, i.e., protein regions that are major contributors to the binding free energy. The main tool of the analysis is computational solvent mapping, which explores the surface of proteins by docking a large number of small "probe" molecules. Although we consider conformational ensembles obtained by NMR techniques, the analysis is independent of the method used for generating the structures. Finding the energetically most important regions, mapping can identify binding site residues using ligand-free models based on NMR data. In addition, the method selects conformations that are similar to some peptide-bound or ligand-bound structure in terms of the properties of the binding site. This agrees with the conformational selection model of molecular recognition, which assumes such pre-existing conformations. The analysis also shows the maximum level of similarity between unbound and bound states that is achieved without any influence from a ligand. Further shift toward the bound structure assumes protein-peptide or protein-ligand interactions, either selecting higher energy conformations that are not part of the NMR ensemble, or leading to induced fit. Thus, forming the sites in protein-protein interfaces that bind peptides and can be targeted by small ligands always includes conformational selection, although other recognition mechanisms may also be involved.

Dataset Information

Discovery of novel helix binding sites at protein-protein interfaces.

Publications

Discovery of novel helix binding sites at protein-protein interfaces.

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