Browsing by Author "Freedman, Holly"
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- Computational predictions of volatile anesthetic interactions with the microtubule cytoskeleton: implications for side effects of general anesthesiaPublication . Craddock, Travis J. A.; George, Marc St.; Freedman, Holly; Barakat, Khaled H.; Damaraju, Sambasivarao; Hameroff, Stuart; Tuszynski, Jack A.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.
- Erratum: Mixed quantum-classical dynamics of an amide-I vibrational excitation in a protein a-helix [Phys. Rev. B 82, 174308 (2010)]Publication . Freedman, Holly; Martel, Paulo; Cruzeiro, LeonorIn the GROMACS codemodifications, instead of the nanometer unit for the distance that is standard in GROMACS, a unit of 1 °A was previously assumed. This led to dipole-dipole interactions between amide I vibrations at different sites and the interaction energies of the amide I vibration with the protein hydrogen bonds being overestimated, respectively, by three orders and by one order of magnitude.
- Mixed quantum-classical dynamics of an amide-I vibrational excitation in a protein a-helixPublication . Freedman, Holly; Martel, Paulo; Cruzeiro, LeonorAdenosine triphosphate sATPd is known to be the main energy currency of the living cell, and is used as a coenzyme to generate energy for many cellular processes through hydrolysis to adenosine diphosphate sADPd,although the mechanism of energy transfer is not well understood. It has been proposed that following hydrolysis of the ATP cofactor bound to a protein, up to two quanta of amide-I vibrational energy are excited and utilized to bring about important structural changes in the protein. To study whether, and how, amide-I vibrational excitations are capable of leading to protein structural changes, we have added components arising from quantum-mechanical amide-I vibrational excitations to the total energy and force terms within a moleculardynamics simulation. This model is applied to helical deca-alanine as a test case to investigate how its dynamics differs in the presence or absence of an amide-I excitation. We find that the presence of an amide-I excitation can bias the structure toward a more helical state.
- The temperature dependent amide i band of crystalline acetanilidePublication . Cruzeiro, Leonor; Freedman, HollyThe temperature dependent anomalous peak in the amide I band of crystalline acetanilide is thought to be due to self-trapped states. On the contrary, according to the present model, the anomalous peak comes from the fraction of ACN molecules strongly hydrogen-bonded to a neighboring ACN molecule, and its intensity decreases because, on average, this fraction decreases as temperature increases. This model provides, for the first time, an integrated and theoretically consistent view of the temperature dependence of the full amide I band and a qualitative explanation of some of the features of nonlinear pump–probe experiments.