Docking and molecular dynamics studies of the binding between Peloruside A and tubulin

Abstract

The molecular docking, MD simulation and binding free energy calculation were performed to explore the probable binding modes between PLA and tubulin. Through docking study, three possible binding sites for PLA were speculated as follows: the taxane site, the alternative site and a new site in a-tubulin. Then, 12.0 ns MD simulations show that these binding modes predicted by docking have been changed more or less, whereas the MD simulations offer more reliable binding details. The MM-PBSA binding free-energy calculations reasonably identify that the taxane site is the most favorable binding site of PLA and the alternative site is the secondary one, which can be used to explain some experimental facts. These studies theoretically resolve the priority of binding sites for PLA and offer the reliable binding modes between PLA and tubulin, and thus help to understanding the action mechanism for this kind of inhibitor.

Further Insight into the Interactions of the Cytotoxic Macrolides Laulimalide and Peloruside A with Their Common Binding Site

“…Going further, Figure shows a new model with two α-tubulins and two β-tubulins (α1β1/α2β2, the minimum representative fragment of two adjacent filaments of a microtubule), to evaluate features of the lateral contacts. Other authors have very recently calculated the interactions of tetramers with 1 , or with 2 via other methods. Our blind docking outcomes in the case of 1 are shown in Figure and the results for 2 in Figure .…”

“…The MD simulations were performed with the periodic boundary conditions in the NPT ensemble using OPLS2005 force field parameters; the ligand−β-tubulin and β-tubulin−β-tubulin interactions turned out to be almost identical to those obtained with AMBER. 24−26 The temperature and pressure were kept at 300 K and 1 atm (1013.25 hPa), respectively, using Nose–Hoover temperature coupling and isotropic scaling. Finally, the analysis of the contacts between the two adjacent β-tubulins was done with MDcons.…”

“…In other words, 1 and 2 link two vicinal β-tubulin units (in two different filaments). Calculations concerning this issue by Hamel et al ( 1 and 2 , Glide), 22 by Horwitz and co-workers ( 1 and 2 , AutoDock), 23 and by Liao et al ( 2 , AD4.2 and AMBER 10) 24 are worth noting. Two excellent articles, by Tuszynski et al ( 1 , AMBER 12 and AMBER 14), 25,26 which appeared when the present study with other methods had started, are also key because, as it will be demonstrated herein, our results confirm and complement them.…”

“…Sometimes, three binding sites were found. Liao et al., 24 for instance, found that the tax site was the most favorable for 2 , followed by the ext site and by a new site in α-tubulin, but outside the B9–B10 loop. We cannot repeat or even summarize here all the agreements and divergences, but it is understandable that the use of tubulins arising from different animal sources, the nature of the characterization techniques for such delicate complexes, the features of the cocrystals (sometimes quite artificial in relation to the intracellular world), the disparate calculation methods and their simplifications, and so forth cannot give rise to identical results.…”

Recent Developments and Applications of the MMPBSA Method

“…They also utilized a quantitative structure activity relationship (QSAR) model to improve the correlation to 0.88, combining affinities from MMPBSA, QM/MMGBSA, and Glide scoring (Slynko et al, 2014 ). There were other attractive targets including indoleamine 2,3-dioxygenase 1 (Zou et al, 2017 ), translationally controlled tumor protein (Kumar R. et al, 2017 ), estrogen receptor (Anbarasu and Jayanthi, 2017 ), MutT homolog 1 (Zhou et al, 2016 ), survivin (Sarvagalla et al, 2016 ), CD44 (Nguyen et al, 2016 ), calmodulin (Gonzalez-Andrade et al, 2016 ), androgen receptor (Liu H. L. et al, 2016 ), human topoisomerase I (Guruge et al, 2016 ), Mcl-1 (Zhao et al, 2015 ), vascular endothelial growth factor receptor-2 (Wu et al, 2015 ), tubulin (Liao et al, 2014a , b ; Santoshi and Naik, 2014 ; Suri and Naik, 2015 ; Suri et al, 2015 ), the Hsp70 protein family (Bhattacharjee et al, 2015 ; Schneider et al, 2016 ), the Hsp90 protein family (Arba et al, 2015 ), glucose 6-phosphate dehydrogenase (Obiol-Pardo et al, 2014 ; Zhao et al, 2014 ), lysozyme (Zhan et al, 2015 ), p53 (Verma S. et al, 2016 ), wheat germ agglutinin (Parasuraman et al, 2014 ), bromodomains (Muvva et al, 2014 ), matrix metalloproteinases (Zhou et al, 2014 ), protein arginine methyltransferases (Hong et al, 2014 ; Yan et al, 2014 ), human arsenic methyltransferase (Abro and Azam, 2016 ), Atox1 proteins (Wang X. L. et al, 2014 ), tyrosyl-DNA phosphodiesterase 2 (Kossmann et al, 2016 ), and urokinase-type plasminogen activator (Sa et al, 2014 ).…”