Librational Mode Coupling Theory of Allosteric Signal Transmission

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Project Summary: Libratioal Mode Coupling Theory of Allosteric Signal Transmission The allosteric effect in proteins is the modulation of functional behavior due to interaction with an effector ligand or a mutation at a region distal to the active site. Allostery is a critical feature of all metabolic control processes, the mechanisms of action of biomolecular machines and motors, gene expression, and many other biological phenomena. Notably, the time frame of an allosteric effect is ~10-3 – 1 seconds, but the length scale can be quite long (100 Angstroms in the DNA repair protein, MutS). Recent reviews report diverse examples fn the state of experiment and theory of the allosteric effect in diverse examples, but all concur that the molecular mechanism of allosteric signal propagation in large proteins remains an unsettled research question. Recently (2020) some experiments that can track the time evolution of an allosteric signal have been reported, but remain to be fully interpreted. A number of hypotheses about how allostery works at the molecular level have been proposed, including pathways of cooperative amino acid residues, flexibility/rigidity models, energy landscape - ensemble theory, and complex networks, all of which have some plausibility. However, each has been applied to positive instances in only one or just a few proteins in a class, and typically do not include statistical controls nor explain ligand binding or mutations which have potential but do not elicit an allosteric effect (negative instances). A particular challenge with large proteins has been accounting for the propagation of allosteric signals over long range without attenuation. A promising hypothesis pursued here postulates that long-range signal transmission occurs as an allosteric effector-induced perturbation transmitted via coupling with the delocalized breathing motions of a protein, i.e. “librational mode coupling” (LMC). The proposed research involves elucidating the extent to which LMC contributes to allosteric signaling using “state-of-the-art" all- atom molecular dynamics (MD) computer simulations together with our LMC analysis, considering both motional and energy options for obtaining modes. The specific objective of this proposal is the development and testing of a quantitative metric diagnostic of allosteric signal propagation via LMC as applied to MD simulations on selected, well-characterized allosteric proteins. The results of the proposed LMC-MD studies may either support or refute the role of breathing motions, with either outcome contributing valuable new knowledge. Success of this project will result in new fundamental knowledge about allosteric control processes that will be ultimately useful in allosteric drug design.