Microtubules dual chemo and thermo-responsive depolymerization

The effects of chemotherapeutic agent vinblastine versus low temperature of 277 K were investigated on the structure of αβ-tubulin heterodimer by means of molecular dynamics simulations. Individual experiments have shown that the vinblastine-bound heterodimer, and its apo structure under low temperature of 277 K, both undergo conformational changes toward destabilization of the dimer as compared to the apo tubulin at 300 K. Both factors exhibited weakening of the longitudinal interactions of tubulin heterodimer through displacing dimer interfacial segments, resulting in dominant electrostatic repulsion at the interface of the subunits. The two independent factors of temperature and anti-mitotic agent facilitate alteration of secondary structure in functional segments such as H1-S2 loop, H3, H10 helices, and T7 loop, which are known to be important in either longitudinal or lateral contacts among αβ-heterodimers in MTs protofilaments and their depolymerization mechanism. Proteins 2015; 83:970–981. © 2015 Wiley Periodicals, Inc.