Exploring ligand binding pathways on proteins using hypersound-accelerated molecular dynamics

Mitsugu Araki (), Shigeyuki Matsumoto, Gert-Jan Bekker, Yuta Isaka, Yukari Sagae, Narutoshi Kamiya and Yasushi Okuno ()
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Mitsugu Araki: Graduate School of Medicine, Kyoto University
Shigeyuki Matsumoto: Medical Sciences Innovation Hub Program, RIKEN Cluster for Science, Technology and Innovation Hub
Gert-Jan Bekker: Institute for Protein Research, Osaka University
Yuta Isaka: Research and Development Group for In Silico Drug Discovery, Center for Cluster Development and Coordination (CCD), Foundation for Biomedical Research and Innovation at Kobe (FBRI)
Yukari Sagae: Graduate School of Medicine, Kyoto University
Narutoshi Kamiya: Graduate School of Simulation Studies, University of Hyogo
Yasushi Okuno: Graduate School of Medicine, Kyoto University

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: Abstract Capturing the dynamic processes of biomolecular systems in atomistic detail remains difficult despite recent experimental advances. Although molecular dynamics (MD) techniques enable atomic-level observations, simulations of “slow” biomolecular processes (with timescales longer than submilliseconds) are challenging because of current computer speed limitations. Therefore, we developed a method to accelerate MD simulations by high-frequency ultrasound perturbation. The binding events between the protein CDK2 and its small-molecule inhibitors were nearly undetectable in 100-ns conventional MD, but the method successfully accelerated their slow binding rates by up to 10–20 times. Hypersound-accelerated MD simulations revealed a variety of microscopic kinetic features of the inhibitors on the protein surface, such as the existence of different binding pathways to the active site. Moreover, the simulations allowed the estimation of the corresponding kinetic parameters and exploring other druggable pockets. This method can thus provide deeper insight into the microscopic interactions controlling biomolecular processes.

Date: 2021
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DOI: 10.1038/s41467-021-23157-1

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