Premium
Molecular modeling study on the differential microtubule‐stabilizing effect in singly‐ and doubly‐bonded complexes with peloruside A and paclitaxel
Author(s) -
Zúñiga Matías A.,
Alderete Joel B.,
Jaña Gonzalo A.,
Navarrete Karen R.,
Jiménez Verónica A.
Publication year - 2019
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.25692
Subject(s) - microtubule , tubulin , paclitaxel , molecular dynamics , cytoskeleton , biophysics , chemistry , stereochemistry , crystallography , cell , biochemistry , biology , computational chemistry , microbiology and biotechnology , chemotherapy , genetics
Microtubules (MT) are dynamic cytoskeletal components that play a crucial role in cell division. Disrupting MT dynamics by MT stabilizers is a widely employed strategy to control cell proliferation in cancer therapy. Most MT stabilizers bind to the taxol (TX) site located at the luminal interface between protofilaments, except laulimalide and peloruside A (PLA), which bind to an interfacial pocket on outer MT surface. Cryo‐electron microscopy MTs reconstructions have shown differential structural effects on the MT lattice in singly‐ and doubly‐bonded complexes with PLA, TX, and PLA/TX, as PLA is able to revert the lattice heterogeneity induced by TX association leading to more regular MT assemblies. In this work, fully‐atomistic molecular dynamics simulations were employed to examine the single and double association of MT stabilizers to reduced MT models in the search for structural and energetic evidence that could be related to the differential regularization and stabilization effects exerted by PLA and TX on the MT lattice. Our results revealed that the double association of PLA/TX (a) strengthens the lateral contact between tubulin dimers compared to singly‐bonded complexes, (b) favors a more parallel arrangement between tubulin dimers, and (c) induces a larger restriction in the interdimeric conformational motion increasing the probability of finding structures consistent with 13‐protofilaments arrangements. These results and are valuable to increase understanding about the molecular mechanism of action of MT stabilizers, and could account for an overstabilization of MTs in doubly‐bonded complexes compared to singly‐bonded systems.