Effect of Anesthetics on Collective London Dispersion Oscillations in Tubulin and its Implications for PostOperative Cognitive Dysfunction
Event Location / Date(s)
Conference Name / Publication Title
QuEBS 2017: Workshop on Quantum Effects in Biological Systems
Background: Tubulin and the microtubule cytoskeleton are often overlooked sites of anesthetic action and side effects; however, many recent studies have indicated direct interactions between anesthetics and microtubules. The physicochemical mechanisms of volatile general anesthetics have been studied for many years, with general agreement that no chemical reaction seems to take place, and that their action is due to physical rather than chemical actions of the molecules. While the exact mechanisms and sites of action for anesthetics are unknown, it is well accepted that the effect of anesthetics is related to their hydrophobicity, dipolarity, and polarizability. The MeyerOverton correlation most commonly exemplifies the link between the potency of an anesthetic and its lipid solubility. Not surprisingly, there is good correlation between anesthetic potency and molecular properties that are determined by relatively weak long-range interactions, including molar refraction, molal volume, solubility in olive oil, and of particular importance, the polarizability of the anesthetic agent. Correlation of anesthetic activity with the van der Waals (vdW) cohesive forces between molecules and molecular volume constants supports the importance of vdW forces in anesthetic action.
Hypothesis: We hypothesize that anesthetics can alter London force-mediated oscillations of induced dipoles on aromatic amino acids in non-polar, hydrophobic regions of proteins. This effect is due to the polarizability and permanent dipole moments of anesthetics. Protein hydrophobic regions are primarily composed of the aliphatic and aromatic amino acids, with the aromatics tryptophan, tyrosine and phenylalanine all being highly polarizable and therefore susceptible to influence by anesthetic dipoles. As dispersion forces contribute to protein folding and tend to be stronger between molecules that are easily polarized, the effect of anesthetic polarizability on binding to proteins has implications for the dynamics of protein interactions.
Methods: We use results of previous anesthetic binding site predictions on tubulin, along with molecular docking, quantum chemistry calculations, and theoretical modeling of collective dipole interactions to investigate the effect of molecular polarizabilities of anesthetics and non-anesthetics on the function of tubulin.
Results: Our results show that the polarizability of the eight anesthetic molecules investigated follows the Meyer-Overton correlation, while two of three non-anesthetics deviate from this trend. The same two non-anesthetics also fail to bind to key pockets within the tubulin protein. Induced dipoles of amino acids in tubulin alone generate normal mode oscillations in the 3-4.5 x 1015 rad/s frequency range. Binding of anesthetics and nonanesthetics all introduced new frequency modes, correlating with their experimental and predicted anesthetic potency, in the 1015 rad/s magnitude range. Finally, all anesthetics shift specific normal modes of tubulin by approximately 1010 – 1012 rad/s, which follows a trend associated with their anesthetic potency. These shifts have implications for overall protein function and polymerization.
Conclusion: As this mechanism has bearing on the link between anesthesia, postoperative cognitive dysfunction, and neurodegenerative disease, it has the potential to provide new insights on the site and mechanism of anesthetic action and side effects, and may also lead to the design and development of novel anesthetics free of potentially deleterious effects.
Craddock, T. J.,
Hameroff, S. R.,
Tuszynski, J. A.
(2017). Effect of Anesthetics on Collective London Dispersion Oscillations in Tubulin and its Implications for PostOperative Cognitive Dysfunction. QuEBS 2017: Workshop on Quantum Effects in Biological Systems.
Available at: https://nsuworks.nova.edu/cps_facpresentations/3557