Contact rearrangements form coupled networks from local motions in allosteric proteins

Abstract

Allosteric proteins bind an effector molecule at one site resulting in a functional change at a second site. We hypothesize that networks of contacts altered, formed, or broken are a significant contributor to allosteric communication in proteins. In this work, we identify which interactions change significantly between the residue-residue contact networks of two allosteric structures and then organize these changes into graphs. We perform the analysis on 15 pairs of allosteric structures with effector and substrate each present in at least one of the two structures. Most proteins exhibit large, dense regions of contact rearrangement, and the graphs form connected paths between allosteric effector and substrate sites in five of these proteins. In the remaining ten proteins, large-scale conformational changes such as rigid-body motions are likely required in addition to contact rearrangement networks to account for substrate-effector communication. On average, clusters which contain at least one substrate or effector molecule comprise 20% of the protein. These allosteric graphs are small worlds; that is, they typically have mean shortest path lengths comparable to those of corresponding random graphs and average clustering coefficients enhanced relative to those of random graphs. The networks capture 60 to 80% of known allosteryperturbing mutants in three proteins, and the metrics degree and closeness are statistically good discriminators of mutant residues from non-mutant residues within the networks in two of these three proteins. For two proteins, coevolving clusters of residues which have been hypothesized to be allosterically important differ from the regions with the most contact rearrangement. Residues and contacts which modulate normal mode fluctuations also often participate in the contact rearrangement networks. In summary, residue-residue contact rearrangement networks provide useful representations of the portions of allosteric pathways resulting from coupled local motions.

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

“…Another study identified those conserved residues that had the largest contribution to maintaining short paths within the protein structure network; the results showed good agreement with experimental findings for 7 protein families [57]. 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].…”

“…• Network-based analysis of perturbation propagation is a fruitful method to identify intra-protein allosteric pathways [21,44,45,[59][60][61]71,93,97,102,111,127,208]. A successful candidate for the inter-protein allosteric pathways involved in allo-network drug action disturbs network perturbations specific to a disease state of the cell at a site distant from the original drug-binding site.…”

Computational Studies of Allosteric Regulation in the Hsp90 Molecular Chaperone: From Functional Dynamics and Protein Structure Networks to Allosteric Communications and Targeted Anti‐Cancer Modulators

“…[51,54] Small-world allosteric networks and long-range communications in proteins appeared to be primarily governed by spatially separated clusters of specific functional residues. [55][56][57] These studies suggested that rapid transmission of allosteric interactions through small-world networks encoded in protein folds may have been a universal requirement encoded across diverse protein families.…”

Strain analysis of protein structures and low dimensionality of mechanical allosteric couplings

“…Some attempts have been made along these lines. Daily et al (23) analyzed networks of contact rearrangements to find regions of the protein proposed to transmit structural rearrangements between allosteric and active sites. Some attempts to use normal mode analysis to study relationships between residue mobility and allostery have been made (24,25), and Miyashita et al (26) attempted to estimate deformation energies of the elastic network model.…”