Robert S. Cantor
Professor of Chemistry
Professor Cantor received his B.S. degree in Physics in 1975 from Yale University and the Ph.D. degree in Chemistry at M.I.T. in 1979, working with J. S. Waugh on topics in the theory of spin dynamics. Post-doctoral study in polymer solution theory with P. G. deGennes at the Collège de France was followed by application of polymer methodology to the statistical thermodynamics of lipid monolayers and bilayers, working with K. A. Dill at the University of Florida and at the University of California, San Francisco. In 1984, he joined the faculty of Dartmouth College. In 2002, he was appointed to the International Faculty of the University of Southern Denmark in Odense, and in 2004 was elected a foreign member of the Royal Danish Society of Sciences and Letters.
Research Interests
- go to Research Group Web Site for details -
Lipid bilayers and the molecular mechanism of anesthesia. The function of many intrinsic membrane proteins requires a conformational transition that is often strongly influenced by the molecular composition of the bilayer in which the protein is embedded. A nonlocal, indirect mechanism for this shift in conformational equilibrium has been suggested [1-3], in which it is argued that a redistribution of lateral pressures of the bilayer resulting from a change in lipid composition alters the amount of mechanical work of the protein conformational transition. Calculations have suggested possible roles of cholesterol, highly unsaturated fatty acids and small solutes in modulating membrane protein function. In particular, lattice statistical mechanical calculations have been used to predict the effects of small solutes of varying interfacial activity on the pressure distribution, resulting in a novel bilayer-mediated (i.e., indirect) molecular mechanism of anesthesia. This approach predicts [6] some of the well-known failures of the Meyer-Overton correlation: the anomolously low anesthetic potency of molecules which are highly soluble in membranes, e.g., overly hydrophobic molecules such as perfluorinated alkanes as well as long-chain n-alkanols. It was argued that long-chain polyhydric alkanols should serve as an unambiguous test to distinguish between an indirect and a direct binding mechanism in which chain-length cutoff arises from steric hindrance, because such alkanols would only be predicted to be potent anesthetics in the context of the indirect mechanism, as they would far exceed the volume of a proteinaceous site. Two such synthetic alcohols, 1,6,11,16-hexadecanetetraol and 2,7,12,17-octadecanetetraol, have been shown [9] to have anesthetic potency on tadpoles, in strong support of this bilayer-mediated mechanism.
Unfortunately, there is little direct information on the change in shape of the transmembrane region of membrane proteins. It is thus useful to consider various geometric models of such conformational transitions [4]. For both a generic model, and specific models that describe likely cooperative rearrangements of alpha-helices in bundles, it is found that the conformational equilibrium depends on the first and second integral moments of the lateral pressure distribution. In addition to revealing the possible physical underpinnings of the well-known correlation between protein activity and the "non-lamellar" tendency of bilayer lipids, this dependence on moments of the pressure profile allows for prediction of the relative effects of different lipid compositional changes even in the absence of information on specific protein shape changes.
Some membrane peptides form barrel-stave aggregates with a broad size distribution that depends on bilayer composition. In analogy to effects on conformational equilibria in membrane proteins, this effect can be understood as a coupling of shifts in the distribution of lateral pressures in the bilayer to depth-dependent changes in the lateral excluded area that accompanies the formation of an aggregate. Thermodynamic analysis using a simple geometric model of aggregates of kinked cylindrical peptides is employed to predict the effects of changes in bilayer characteristics on aggregate size distributions, in qualitative agreement with experiment [7].
When the common practice of fitting dose-response data to the Hill equation is applied to the predictions of the pressure-profile mechanism, the fits are found to be reasonably good, with large Hill coefficients [5]. Since this would commonly be interpreted as evidence of the existence of multiple sites with strong positive cooperativity, it is argued that caution must therefore be exercised in the interpretation of titration data in the absence of direct evidence of the existence of binding sites.
Anesthesia and synaptic transmission: are neurotransmitters the endogenous anesthetics? In a recent study [8], a novel mechanistic hypothesis for the modulation of currents of post-synaptic ligand-gated ion channels has been suggested. If this mechanism proves correct, it would have broad implications for the molecular mechanism of general anesthesia, and in particular, it could explain perhaps the most peculiar aspect of anesthesia: the remarkably small variability of sensitivity within the human population and among a broad range of animal phyla.
It is hypothesized that in addition to the rapid, saturable binding of a neurotransmitter to its receptor that results in activation, the neurotransmitter also acts indirectly on the receptor by interacting with the postsynaptic membrane and changing its physical properties, causing a gradual shift in receptor conformational equilibria. Unlike binding, this slower membrane-mediated mechanism is fairly nonspecific. Predicted time-dependent ion currents are found to exhibit many of the characteristics of functional desensitization and deactivation observed electrophysiologically, both for inhibitory and excitatory channels, including the dependence on neurotransmitter concentration. If receptors have evolved to regulate the time course of ion currents by this mechanism then (a) mutations that significantly alter receptor sensitivity to this effect would be lethal and (b) by design, excitatory receptors would be inhibited, but inhibitory receptors activated, so that their effects are not counterproductive. The wide range of exogenous molecules that affect the physical properties of membranes as do neurotransmitters, but which do not bind to receptors, would thus inhibit excitatory channels and activate inhibitory channels, i.e., they would act as anesthesics. The endogenous anesthetics would thus be the neurotransmitters, the survival advantage conferred by their proper membrane-mediated desensitization and deactivation of receptors explaining the selection pressure for anesthesic sensitivity.
The plausibility of this proposed mechanism is being studied using a range of experimental and computational methodologies, in collaboration with colleagues at the Memphys Center for Biomembrane Physics at the University of Southern Denmark. The interactions of fast neurotransmitters and anesthetics with lipid bilayers are being investigated using molecular dynamics (MD) simulations, calorimetry, fluorescence, monolayer films, and micromechanical measurements.