Anesthetic Alterations of Collective Terahertz Oscillations in Tubulin Correlate with Clinical Potency: Implications for Anesthetic Action and Post-Operative Cognitive Dysfunction

Abstract

Anesthesia blocks consciousness and memory while sparing non-conscious brain activities. While the exact mechanisms of anesthetic action are unknown, the Meyer-Overton correlation provides a link between anesthetic potency and solubility in a lipid-like, non-polar medium. Anesthetic action is also related to an anesthetic's hydrophobicity, permanent dipole, and polarizability, and is accepted to occur in lipid-like, non-polar regions within brain proteins. Generally the protein target for anesthetics is assumed to be neuronal membrane receptors and ion channels, however new evidence points to critical effects on intra-neuronal microtubules, a target of interest due to their potential role in post-operative cognitive dysfunction (POCD). Here we use binding site predictions on tubulin, the protein subunit of microtubules, with molecular docking simulations, quantum chemistry calculations, and theoretical modeling of collective dipole interactions in tubulin to investigate the effect of a group of gases including anesthetics, non-anesthetics, and anesthetic/convulsants on tubulin dynamics. We found that these gases alter collective terahertz dipole oscillations in a manner that is correlated with their anesthetic potency. Understanding anesthetic action may help reveal brain mechanisms underlying consciousness, and minimize POCD in the choice and development of anesthetics used during surgeries for patients suffering from neurodegenerative conditions with compromised cytoskeletal microtubules.

Figure 1

Chemical structure of investigated agents. Blue – anesthetics; Red - non-anesthetics; Green – anesthetic/convulsant.

Figure 2

Correlation of anesthetic properties with anesthetic potency. (a) Meyer-Overton correlation of oil:gas partition coefficient versus MAC (Blue points – anesthetics; Red points – non-anesthetics; Green points – anesthetic/convulsant; Red line – difference between non-anesthetic predicted and estimated (~1000% atm) MAC). (b) Correlation of polarizability versus MAC, with MAC for non-anesthetics determined from the Meyer-Overton correlation. (c) Correlation of polarizability versus solubility shows a difference in the relation between these properties for non-anesthetics and anesthetics. Trend lines and equations based on anesthetics alone, without the contributions from the non-anesthetics and anesthetic/convulsant.

Figure 3

Collective dipole modes of oscillation in tubulin. (a) Average energies of the collective dipole modes of oscillation in tubulin. Gray – normal modes predicted for tryptophan, tyrosine and phenylalanine in tubulin in the absence of agents. (Blue – additional normal modes introduced due to the presence of an anesthetic agent; Red - additional normal modes introduced due to the presence of a non-anesthetic agent; Green – additional normal mode introduced to the presence of the anesthetic/convulsant agent flurothyl). (b) Agent-induced new frequency modes of oscillation versus MAC. As the non-anesthetics fall below the trend line minimum there is no predicted MAC for non-anesthetics available at any value. (Blue points – anesthetics; Red points - non-anesthetics; Green points – anesthetic/convulsant; Red line – difference between non-anesthetic predicted and actual (~1000% atm) MAC).

Figure 4

Change in tubulin collective dipole modes due to the addition of anesthetic/non-anesthetic molecules for different binding sites. (a) Site specific changes for anesthetics and anesthetic/convulsant flurothyl shows a prominent downwards shift at (613 ± 8) THz, while non-anesthetics F6 and TFMB show an increase at this frequency band. (b) Maximum agent induced change in tubulin normal mode oscillation frequency at (613 ± 8) THz versus agent MAC. (Blue points – anesthetics; Red points - non-anesthetics; Green points – anesthetic/ convulsant).