Structural insight into the role of Gln293Met mutation on the Peloruside A/Laulimalide association with αβ-tubulin from molecular dynamics simulations, binding free energy calculations and weak interactions analysis

Matías A. Zúñiga, Joel B. Alderete, Gonzalo A. Jaña, Verónica A. Jiménez

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

Peloruside A (PLA) and Laulimalide (LAU) are novel microtubule-stabilizing agents with promising properties against different cancer types. These ligands share a non-taxoid binding site at the outer surface of β-tubulin and promote microtubule stabilization by bridging two adjacent αβ-tubulin dimers from parallel protofilaments. Recent site-directed mutagenesis experiments confirmed the existence of a unique β-tubulin site mutation (Gln293Met) that specifically increased the activity of PLA and caused resistance to LAU, without affecting the stability of microtubules in the absence of the ligands. In this work, fully atomistic molecular dynamics simulations were carried out to examine the PLA and LAU association with native and mutated αβ-tubulin in the search for structural and energetic evidence to explain the role of Gln293Met mutation on determining the activity of these ligands. Our results revealed that Gln293Met mutation induced the loss of relevant LAU–tubulin contacts but exerted negligible changes in the interaction networks responsible for PLA–tubulin association. Binding free energy calculations (MM/GBSA and MM/PBSA), and weak interaction analysis (aNCI) predicted an increased affinity for PLA, and a weakened association for LAU after mutation, thus suggesting that Gln293Met mutation exerts its action by a modulation of drug–tubulin interactions. These results are valuable to increase understanding about PLA and LAU activity and to assist the future design of novel agents targeting the PLA/LAU binding pocket.

Original languageEnglish
Pages (from-to)643-652
Number of pages10
JournalJournal of Computer-Aided Molecular Design
Volume31
Issue number7
DOIs
Publication statusPublished - 1 Jul 2017

Keywords

  • Binding free energy
  • Gln293Met mutation
  • Laulimalide
  • Microtubule-stabilizing agents
  • Molecular dynamics
  • Peloruside A
  • Weak interaction analysis

ASJC Scopus subject areas

  • Drug Discovery
  • Computer Science Applications
  • Physical and Theoretical Chemistry

Fingerprint

Dive into the research topics of 'Structural insight into the role of Gln293Met mutation on the Peloruside A/Laulimalide association with αβ-tubulin from molecular dynamics simulations, binding free energy calculations and weak interactions analysis'. Together they form a unique fingerprint.

Cite this