Computational study of microtubule stability and associated chemotherapeutic agents

Abstract

Microtubules are cellular structures that are crucial to many cellular functions including maintenance of cell shape, vesicular transport, and cell division. The dynamic instability of microtubules is the basic feature which enables them to do their cellular functions. Their pivotal role in cell division makes them an important therapeutic target for cancer chemotherapeutic treatment. In this thesis, I have studied two major biological problems connected to microtubules: virtual screening for novel microtubule stabilizing agents, and energetic analysis of tubulin inter-dimer binding energies within microtubules. In the virtual screening project a library of 33 million chemical compounds was screened against available microtubule stabilizing agents using similarity fingerprints and structure-based drug design techniques arriving at a novel scaffold predicted to bind at the taxol binding site. This novel scaffold shed light on the mechanism of antitumor action of lankacidin antibiotics, due to sharing a high degree of similarity, and was tested and partly confirmed computationally and experimentally. In the microtubule energetic analysis project, various quantum chemical descriptors were tested and parameterized for the prediction of hydrogen bond energies. These descriptors and parameters were used in analyzing the strength of hydrogen bonds across the longitudinal inter-dimer interfaces through which tubulin dimers join head-to-tail to form protofilaments, and across the lateral inter-dimer interface through which protofilaments align side-by-side to form microtubule cylinders. As a continuation to this study, a molecular dynamics simulation of a complete microtubule was run, followed by a complete analysis and breakdown of MM/GBSA (Molecular Mechanics/Generalized Born-Surface Area) binding energies at lateral and longitudinal inter-dimer interfaces enabling thorough analysis of the contribution of each residue, domain, subunit, and dimer to the stability of a microtubule cylinder and shedding light on the driving force for microtubule disassembly and other important phenomena.