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The Unique Binding Mode of Laulimalide to Two Tubulin Protofilaments
Author(s) -
Churchill Cassandra D. M.,
Klobukowski Mariusz,
Tuszynski Jack A.
Publication year - 2015
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12475
Subject(s) - tubulin , microtubule , chemistry , plasma protein binding , biophysics , binding site , molecular dynamics , computational biology , biology , microbiology and biotechnology , biochemistry , computational chemistry
Laulimalide, a cancer chemotherapeutic in preclinical development, has a unique binding site located on two adjacent β ‐tubulin units between tubulin protofilaments of a microtubule. Our extended protein model more accurately mimics the microtubule environment, and together with a 135 ns molecular dynamics simulation, identifies a new binding mode for laulimalide, which differs from the modes presented in work using smaller protein models. The new laulimalide–residue interactions that are computationally revealed explain the contacts observed via independent mass shift perturbation experiments. The inclusion of explicit solvent shows that many laulimalide–tubulin interactions are water mediated. The new contacts between the drug and the microtubule structure not only improve our understanding of laulimalide binding but also will be essential for efficient derivatization and optimization of this prospective cancer chemotherapy agent. Observed changes in secondary protein structure implicate the S7–H9 loop ( M –loop) and H1′–S2 loop in the mechanism by which laulimalide stabilizes microtubules to exert its cytotoxic effects.