College of Psychology: Faculty Articles

Title

Computational Predictions of Volatile Anesthetic Interactions with the Microtubule Cytoskeleton: Implications for Side Effects of General Anesthesia

Document Type

Article

Publication Date

6-25-2012

Keywords

General Anesthesia, Drug-Related Side Effects and Adverse Reactions, Neurodegenerative Diseases, Cytoskeleton, Halothane, Microtubules, Chemical Models, Tubulin, Protein Conformation, Computer Simulation

Publication Title

PLoS One

ISSN

1932-6203

Volume

7

Issue/No.

6

Abstract

The cytoskeleton is essential to cell morphology, cargo trafficking, and cell division. As the neuronal cytoskeleton is extremely complex, it is no wonder that a startling number of neurodegenerative disorders (including but not limited to Alzheimer’s disease, Parkinson’s disease and Huntington’s disease) share the common feature of a dysfunctional neuronal cytoskeleton. Recently, concern has been raised about a possible link between anesthesia, post-operative cognitive dysfunction, and the exacerbation of neurodegenerative disorders. Experimental investigations suggest that anesthetics bind to and affect cytoskeletal microtubules, and that anesthesia-related cognitive dysfunction involves microtubule instability, hyper-phosphorylation of the microtubule-associated protein tau, and tau separation from microtubules. However, exact mechanisms are yet to be identified. In this paper the interaction of anesthetics with the microtubule subunit protein tubulin is investigated using computer-modeling methods. Homology modeling, molecular dynamics simulations and surface geometry techniques were used to determine putative binding sites for volatile anesthetics on tubulin. This was followed by free energy based docking calculations for halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) on the tubulin body, and C-terminal regions for specific tubulin isotypes. Locations of the putative binding sites, halothane binding energies and the relation to cytoskeleton function are reported in this paper.

Comments

This is a copy of an open-access article distributed under the terms of the Creative Commons Attribution License.

DOI

10.1371/journal.pone.0037251