Michael V. LeVine

Information Processing and Allostery in Biomolecular Systems

Research Summary:
The research group is interested in understanding the mechanisms underlying informational processing in biomolecular systems. Biomolecular information processing is accomplished through allostery, the phenomenon in which two or more molecular processes, sometimes separated by large distances in a molecular assembly, are thermodynamically coupled. Allostery has proven to be ubiquitous throughout biology, playing a central role in many essential biological functions. Most notably, allostery has been shown to be a crucial component of cell signaling in general, and neurotransmission in particular. Membrane proteins are often involved in transmembrane information transmission and processing, exchanging information between the inside and the outside of the cell. For example, G-protein coupled receptors (GPCRs) receive input signals from the extracellular environment by binding small molecules such as neurotransmitters, transmit the presence of those extracellular signals through conformational and dynamical changes throughout their structure, and then produce an output signal by activating, inhibiting, or modulating intracellular processes appropriately, such that cellular signaling can commence and the cell can respond and adapt. This biomolecular information processing can be quite complex; it is now known that receptors can be i) promiscuous, i.e. able to bind a large number of chemical diverse molecules, ii) pleiotropic, i.e. able to modulate the function of a diverse array of effectors, and iii) functionally selective, i.e. able to activate difference downstream signaling responses for different inputs. This type of allosteric complexity occurs in many other membrane proteins, such as transporters, and is crucial to the action of many drugs, both therapeutic (e.g. antidepressants that target the serotonin, dopamine, and norepinephrine transporters) and abused (e.g. hallucinogens that target the serotonin 2A receptor). Due to the importance of allostery in biological information processing, and the inherent complexity observed in physiological systems, rigorous formalisms are required that can define both i) the conditions that are necessary and/or sufficient for allostery and ii) the relationship between information processing and allosteric coupling. The group utilizes statistical mechanics and thermodynamics, information and probability theory, and network and graph theory to construct new models for allostery, both theoretical and computational, in order to derive novel analytical relationships between allostery in general and to understand which structural components and interactions are essential in specific allosteric systems of interest. These methods are constructed specifically for utilization in multidisciplinary collaborations with experimentalists, and we continue to improve on these models so that they can scale the continuum from physics to phenotype.