<title>Author Summary</title> <p>Allosteric regulation is a major mechanism of control in many biological processes, including cell signaling, gene regulation, and metabolic regulation, and malfunctioning allosteric proteins are often involved in cancer and other diseases. In allostery, an effector-binding signal transmits over a long distance through the protein structure, resulting in a functional change at a second site. While many three-dimensional structures of allosteric proteins have been solved, the allosteric communication mechanism is usually not obvious from the motions between inactive and active state structures. In addition, allosteric structural transitions involve both small-scale motions at the level of amino acid residues and large-scale motions at the level of domains. Here, to address allosteric mechanisms, we transform the aforementioned protein motions into a multi-scale “global communication network” (GCN) representation from which substrate-effector pathways and other important allosteric communication properties can be identified. The GCN accounts for substrate-effector pathways in 15 of 18 proteins surveyed, and the GCN reveals that allostery often depends on linkage between the small- and the large-scale motions. This work will inform a wide variety of experiments investigating allostery, and it proposes concepts for engineering allostery into non-allosteric proteins.</p>
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