Laulimalide, which binds to �-tubulin to cause mitotic arrest and apoptosis, is currently in preclinical development as a potential cancer chemotherapy. Within microtubules, this drug binds between adjacent tubulin units, requiring a large protein model to obtain accurate binding information. An improved computational model of Laulimalide binding to a�-tubulin is reported, which better mimics the binding of this drug in microtubules. Molecular dynamics simulations find a unique binding mode for Laulimalide, identifying different drug-residue interactions than those reported previously using a smaller model. These observed contacts are supported by independent mass-shift perturbation experiments. The identification of new contacts between the drug and the microtubule structure improves our understanding of Laulimalide binding, and will be important for derivatizing and optimizing this investigational cancer chemotherapy agent. A proposal for the mechanism by which Laulimalide alters the stability of microtubules is also presented. 

Potential anticancer agent, Laulimalide, binding to tubulin protofilaments

247th National Meeting (2014)

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