[Seminar] Mechanistic Insights into Peptide Recognition by Abl Kinase for Therapeutic Peptide Design by Dr. Ai Shinobu, WPI-PRIMe, Osaka University

Mechanistic Insights into Peptide Recognition by Abl Kinase for Therapeutic Peptide Design

Peptides represent an important class of therapeutic agents due to their ability to mimic protein interactions while retaining high specificity and affinity. Their potential to modulate protein-protein interactions makes them valuable candidates for drug design and mechanistic studies. However, the molecular details of peptide binding remain less understood than those of protein-small molecule interactions because the size and flexibility of peptides present significant sampling challenges for molecular dynamics (MD) simulations.

To address this challenge, we employed two-dimensional replica exchange MD using the gREST/REUS method to investigate the binding of the Abltide substrate peptide to Abl kinase. Enhanced sampling along the binding interface and protein-peptide distance enabled efficient exploration of the recognition process and characterization of the underlying free-energy landscape. The simulations revealed multiple encounter and intermediate states connecting the unbound and bound conformations. The binding landscape was found to be relatively shallow, with the peptide sampling broad regions of the protein surface before reaching the substrate-binding site. Specific hydrophobic and electrostatic contacts contribute to guiding the peptide toward the substrate-binding site.

These findings provide molecular insight into kinase-substrate recognition and establish a framework for the rational design of peptide-based inhibitors. In parallel, the study is being extended toward peptide optimization through mutation free energy perturbation calculations and cyclization strategies, expanding the applicability of the protocol for therapeutic peptide design and, ultimately, the investigation of larger protein-protein interactions.

Reference

Wu, Yichao, and Ai Shinobu. "Protein-peptide binding pathways revealed by two-dimensional replica-exchange molecular dynamics." bioRxiv (2026): 2026-03.

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Dr. Ai Shinobu, Specially Appointed Associate Professor, WPI Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), Osaka University

SHINOBU Ai | PRIMe