Allosteric Communication Occurs via Networks of Tertiary and Quaternary Motions in Proteins

Abstract

Allosteric proteins bind an effector molecule at one site resulting in a functional change at a second site. We hypothesize that allosteric communication in proteins relies upon networks of quaternary (collective, rigid-body) and tertiary (residue–residue contact) motions. We argue that cyclic topology of these networks is necessary for allosteric communication. An automated algorithm identifies rigid bodies from the displacement between the inactive and the active structures and constructs “quaternary networks” from these rigid bodies and the substrate and effector ligands. We then integrate quaternary networks with a coarse-grained representation of contact rearrangements to form “global communication networks” (GCNs). The GCN reveals allosteric communication among all substrate and effector sites in 15 of 18 multidomain and multimeric proteins, while tertiary and quaternary networks exhibit such communication in only 4 and 3 of these proteins, respectively. Furthermore, in 7 of the 15 proteins connected by the GCN, 50% or more of the substrate-effector paths via the GCN are “interdependent” paths that do not exist via either the tertiary or the quaternary network. Substrate-effector “pathways” typically are not linear but rather consist of polycyclic networks of rigid bodies and clusters of rearranging residue contacts. These results argue for broad applicability of allosteric communication based on structural changes and demonstrate the utility of the GCN. Global communication networks may inform a variety of experiments on allosteric proteins as well as the design of allostery into non-allosteric proteins.

Allosteric signal transmission in the nucleotide-binding domain of 70-kDa heat shock protein (Hsp70) molecular chaperones

“…Therefore, not only do perturbations in the nucleotide-binding site affect subdomain interfaces, but also a signal can propagate from subdomain interfaces to the nucleotide-binding site, and in so doing regulate nucleotide binding and ATPase activity. Our results are entirely consistent with a previous hypothesis that allosteric signal transduction occurs via a network of motions of protein modules (e.g., subdomains) (30,31). According to this model, residues at the interfaces between modules form an allosteric network between protein active sites.…”

Surmounting the Cartesian Cut: Klein Bottle Logophysics, The Dirac Algebra and the Genetic Code

“…These adaptable stereochemical modifications point out to the biological importance of topological changes (Rapoport, to appear & 2011c). This is analogous to the link existing between the topological representation of a given network (its wiring diagram, corresponding to the crystal structure of the protein) and the dynamics of the network itself that are supported (but not barely coincident) with its topology (Daily and Gray, 2009), similarly to the dynamical tensegrity structure on which the quantum wave propagation produces embryological development (Rapoport, 2011c).…”

“…As a result, the substrate does not simply bind to a rigid active site; the amino acid side chains which make up the active site are molded into the precise positions that enable the enzyme to perform its catalytic function, evidencing a design-oriented change intrinsic to the present logophysical paradigm (Rapoport, 2011b,c) . IF may enhance the fidelity of molecular recognition in the presence of competition and noise via the conformational proofreading mechanism (Daily and Gray, 2009); yet, what we interpret as 'noise' might be interpreted as structured signaling, in a nested heterarchy of KBs, the HyperKlein Bottle, HKB (Rapoport 2010b(Rapoport , 2011b; this applies as well to evolution.…”

“…protein systems that perform their physiological role without the need of acquiring a well defined 3D structure (Koshland, 1958), lead to enlarge the idea of 'structure' from a specific geometrical pattern to a dynamical non unique configuration (Daily and Gray, 2009). …”

Allo-Network Drugs: Extension of the Allosteric Drug Concept to Protein- Protein Interaction and Signaling Networks

“…For proteins undergoing a clear conformational change due to allostery, pairs of structures can be used to obtain an insight into the allosteric mechanism [93]. It was found that a communication pathway is best identified by combining the network of rigid substructures with the network of contact rearrangements [94].…”