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Open AccessArticle

In Silico Peptide Ligation: Iterative Residue Docking and Linking as a New Approach to Predict Protein-Peptide Interactions

Institut de Chimie Organique et Analytique (ICOA), UMR CNRS-Université d’Orléans 7311, Université d’Orléans BP 6759, 45067 Orléans Cedex 2, France
UMR Physiologie de la Reproduction et des Comportements (INRA, UMR85; CNRS, UMR7247; Université de Tours; IFCE), F-37380 Nouzilly, France
Centre de Biophysique Moléculaire (CNRS UPR4301), Rue Charles Sadron, F-45071 Orléans Cedex 2, France
Author to whom correspondence should be addressed.
Academic Editor: Dragos Horvath
Molecules 2019, 24(7), 1351;
Received: 20 January 2019 / Revised: 2 April 2019 / Accepted: 3 April 2019 / Published: 5 April 2019
(This article belongs to the Special Issue Molecular Docking in Drug Design 2018)
Peptide–protein interactions are corner-stones of living functions involved in essential mechanisms, such as cell signaling. Given the difficulty of obtaining direct experimental structural biology data, prediction of those interactions is of crucial interest for the rational development of new drugs, notably to fight diseases, such as cancer or Alzheimer’s disease. Because of the high flexibility of natural unconstrained linear peptides, prediction of their binding mode in a protein cavity remains challenging. Several theoretical approaches have been developed in the last decade to address this issue. Nevertheless, improvements are needed, such as the conformation prediction of peptide side-chains, which are dependent on peptide length and flexibility. Here, we present a novel in silico method, Iterative Residue Docking and Linking (IRDL), to efficiently predict peptide–protein interactions. In order to reduce the conformational space, this innovative method splits peptides into several short segments. Then, it uses the performance of intramolecular covalent docking to rebuild, sequentially, the complete peptide in the active site of its protein target. Once the peptide is constructed, a rescoring step is applied in order to correctly rank all IRDL solutions. Applied on a set of 11 crystallized peptide–protein complexes, the IRDL method shows promising results, since it is able to retrieve experimental binding conformations with a Root Mean Square Deviation (RMSD) below 2 Å in the top five ranked solutions. For some complexes, IRDL method outperforms two other docking protocols evaluated in this study. Hence, IRDL is a new tool that could be used in drug design projects to predict peptide–protein interactions. View Full-Text
Keywords: protein–peptide interaction; covalent docking; peptide conformation; molecular modeling protein–peptide interaction; covalent docking; peptide conformation; molecular modeling
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MDPI and ACS Style

Diharce, J.; Cueto, M.; Beltramo, M.; Aucagne, V.; Bonnet, P. In Silico Peptide Ligation: Iterative Residue Docking and Linking as a New Approach to Predict Protein-Peptide Interactions. Molecules 2019, 24, 1351.

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