title: Free Energy Profile and Kinetics Studies of Paclitaxel Internalization from the Outer to the Inner Wall of Microtubules.
abstract: Several pieces of experimental evidence led us to hypothesize that the mechanism of action of paclitaxel (Taxol) could involve a two-steps binding process, with paclitaxel first binding within the outer wall of microtubules and then moving into the inner binding site. In this work, we first used multiply targeted molecular dynamics (MTMD) for steering paclitaxel from the outer toward the inner binding site. This rough trajectory was then submitted to a refinement procedure in the path collective variables space. Paclitaxel binding energy was monitored along the refined pathway, highlighting the relevance of residues belonging to the H6-H7 and the M- loops. Computational results were supported by kinetics studies performed on fluorescent paclitaxel derivatives.
authors.affiliation: Dipartimento Farmaco-Chimico Tecnologico, Facoltà di Farmacia, Università degli Studi di Siena , I-53100 Siena, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Maccari
authors.affiliation: Dipartimento Farmaco-Chimico Tecnologico, Facoltà di Farmacia, Università degli Studi di Siena , I-53100 Siena, Italy.|Dipartimento di Chimica e Tecnologia del Farmaco, Università di Roma "La Sapienza" , I-00185 Roma, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Mori
authors.affiliation: Centro de Investigaciones Biológicas , CSIC, 28040 Madrid, Spain.|Centro de Estudios Avanzados de Cuba , La Lisa, Ciudad Habana 17100, Cuba.
authors.forename: Javier
authors.initials: J
authors.lastname: Rodríguez-Salarichs
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences , Beijing 100050, China.
authors.forename: Weishuo
authors.initials: W
authors.lastname: Fang
authors.affiliation: Centro de Investigaciones Biológicas , CSIC, 28040 Madrid, Spain.
authors.forename: José Fernando
authors.initials: JF
authors.lastname: Díaz
authors.affiliation: Dipartimento Farmaco-Chimico Tecnologico, Facoltà di Farmacia, Università degli Studi di Siena , I-53100 Siena, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta