How taxol changes the mechanics of microtubules

Paclitaxel (Taxol) is one of the most widely used chemotherapy drugs. It does not target a gene or a receptor on the cell surface. It acts on the cell’s skeleton: the microtubules, long hollow tubes that hold a cell in shape, serve as tracks for transport inside it, and pull the chromosomes apart when a cell divides.

A skeleton that is always rebuilding

Microtubules are built from a protein called tubulin. Pairs of tubulin units stack end to end into strands, the protofilaments, and the strands sit side by side to close into a tube. In a living cell these tubes keep growing and shrinking, and that constant rebuilding is essential for cell division.

Taxol binds to tubulin and stabilises the tube, so it stops taking itself apart. A cell that cannot remodel its microtubules struggles to divide, which is why the drug is useful against tumours whose cells divide quickly.

A microtubule is also a mechanical object. It bends, vibrates and bears loads, and those properties depend on how its tubulin units are arranged and how firmly they hold on to their neighbours. So we asked a simple question: if taxol changes how tubulin units interact, how does it change the mechanics of the whole tube?

From the pocket to the tube

Taxol sits in a pocket of β-tubulin, one of the two units in each pair. It is the pocket shown on the home page of this site. The problem is one of scale: the drug fills a small pocket in one protein, while the tube it affects is made of many thousands of proteins. No single simulation method covers both.

So we combined three. Atomistic molecular dynamics let us watch the tubulin units move, with and without taxol, atom by atom. Dynamical network analysis traced how motion in one part of the protein is coupled to motion in another, a way of mapping how structural signals travel through it. Finally, an elastic network model, which treats the microtubule as beads joined by springs, let us study how the whole tube vibrates and deforms.

What we found

With taxol bound, a region called the M-loop changed shape. This loop sits where neighbouring protofilaments touch, and in our simulations the new shape made the side-to-side contacts between tubulin units more stable, with more surface in contact.

The pocket itself rearranged too, and the network analysis showed a different pattern of communication through the protein, a sign that motion is passed along different routes when the drug is present.

At the scale of the whole tube, the changed shape of the tubulin pairs and the firmer lateral contacts together gave a tendency towards larger deformations when the microtubule vibrates. In other words, changes in small regions of one protein show up in how the entire structure moves.

Why it matters

Taxol is known to stabilise microtubules, but the chain of events from the binding pocket to the mechanics of the tube is still being worked out. This study links the two, and suggests how changes at the level of single proteins can alter the behaviour of the structure they build.

The approach is not specific to taxol. The same multiscale framework can be applied to other drugs that stabilise microtubules, to compare how each one reshapes the cell’s skeleton.

Read the paper: Cannariato, Zizzi, Tuszynski, Deriu, ACS Biomaterials Science & Engineering 10(9), 5666–5674 (2024). doi:10.1021/acsbiomaterials.4c00847