Binding Mode of Actin–Aplyronine A–Tubulin Heterotrimeric Complex Revealed by Molecular Dynamics Simulation

• Published in: Bulletin of the Chemical Society of Japan Vol. 96; no. 2; pp. 120 - 126
• Main Authors: Utomo, Didik Huswo, Kita, Masaki
• Format: Journal Article
• Language: English
• Published: Tokyo The Chemical Society of Japan 15.02.2023; Chemical Society of Japan
• Subjects: Binding; Lattice vibration; Molecular docking; Molecular dynamics; Proteins; Toxicity; Protein–protein interactions; Antitumor agents; Molecular dynamics simulation
• ISSN: 0009-2673; 1348-0634
• DOI: 10.1246/bcsj.20220299

The antitumor macrolide aplyronine A (ApA) disturbs microtubule (MT) dynamics by inducing the protein–protein interaction (PPI) between actin and tubulin. However, the detailed binding mode of the actin–ApA–tubulin heterotrimeric complex (HTC) and the molecular mechanism by which ApA inhibits MT are unclear. To establish the binding modes of the actin–ApA complex on the tubulin α/β-heterodimer, blind protein–protein docking and molecular dynamics simulations were performed. Two plausible HTC models having enough conformational and ligand stabilities were obtained, in which the C7 N,N,O-trimethylserine ester of ApA, an essential group for its potent cytotoxicity and PPI-inducing effect, interacted with Glu336/Asn337 or Arg123/Glu127 of β-tubulin. Based on the superposed models with the MT lattice, two possible mechanisms were proposed: the HTC would bind to the plus end of MT to potently inhibit tubulin assembly, or the actin–ApA complex would bind to the middle part of MT to form the internal HTC and destabilize MT structure. Our proposed models can explain why the actin–ApA complex inhibits MT dynamics at a much lower concentration than those of fibrous actin and tubulin proteins in cells.