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Our extended protein model more accurately mimics the microtubule environment, and together with a 135\u00a0ns 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\u2013residue interactions that are computationally revealed explain the contacts observed via independent mass shift perturbation experiments. The inclusion of explicit solvent shows that many laulimalide\u2013tubulin 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\u2013H9 loop (<jats:styled-content style=\"fixed-case\">M<\/jats:styled-content>\u2013loop) and H1\u2032\u2013S2 loop in the mechanism by which laulimalide stabilizes microtubules to exert its cytotoxic effects.<\/jats:p>","DOI":"10.1111\/cbdd.12475","type":"journal-article","created":{"date-parts":[[2014,11,6]],"date-time":"2014-11-06T13:19:22Z","timestamp":1415279962000},"page":"190-199","source":"Crossref","is-referenced-by-count":34,"title":["The Unique Binding Mode of Laulimalide to Two Tubulin Protofilaments"],"prefix":"10.1111","volume":"86","author":[{"given":"Cassandra D. 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