A collective motion description of tubulin βT7 loop dynamics

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Tubulin is a protein essential for eukaryotic cell division, forming microtubules.
• Agents disrupting tubulin polymerization are of therapeutic interest for cancer treatment.
• Colchicine inhibits tubulin polymerization by binding to the αβ-tubulin heterodimer interface.

Purpose of the Study:

• To understand the molecular mechanism of tubulin inhibition.
• To investigate the role of the βT7 loop dynamics in tubulin conformation and drug binding.
• To identify key molecular dynamics for developing novel therapeutic agents.

Main Methods:

• Performed 200 ns molecular dynamics simulations of ligand-free αβ-tubulins.
• Utilized principal component analysis (PCA) to identify collective variables describing loop dynamics.
• Analyzed the interaction network associated with the βT7 loop flip and conformational changes.

Main Results:

• Captured the βT7 loop flip dynamics in ligand-free αβ-tubulins.
• Identified two independent collective variables describing the loop flip and its trigger.
• Described the interaction network governing the straight/curved conformational equilibrium of tubulin dimers.

Conclusions:

• The identified collective variables serve as a reaction coordinate for functionally important tubulin dynamics.
• Understanding βT7 loop dynamics provides insights into microtubule assembly and drug interactions.
• This research can guide the development of more effective cancer therapeutics targeting tubulin.