Dependence of prevalence of contiguous pathways in proteins on structural complexity

Abstract

Allostery is a regulatory mechanism in proteins where an effector molecule binds distal from an active site to modulate its activity. Allosteric signaling may occur via a continuous path of residues linking the active and allosteric sites, which has been suggested by large conformational changes evident in crystal structures. An alternate possibility is that the signal occurs in the realm of ensemble dynamics via an energy landscape change. While the latter was first proposed on theoretical grounds, increasing evidence suggests that such a control mechanism is plausible. A major difficulty for testing the two methods is the ability to definitively determine that a residue is directly involved in allosteric signal transduction. Statistical Coupling Analysis (SCA) is a method that has been successful at predicting pathways, and experimental tests involving mutagenesis or domain substitution provide the best available evidence of signaling pathways. However, ascertaining energetic pathways which need not be contiguous is far more difficult. To date, simple estimates of the statistical significance of a pathway in a protein remain to be established. The focus of this work is to estimate such benchmarks for the statistical significance of contiguous pathways for the null model of selecting residues at random. We found that when 20% of residues in proteins are randomly selected, contiguous pathways at the 6 Å cutoff level were found with success rates of 51% in PDZ, 30% in p53, and 3% in MutS. The results suggest that the significance of pathways may have system specific factors involved. Furthermore, the possible existence of false positives for contiguous pathways implies that signaling could be occurring via alternate routes including those consistent with the energetic landscape model.

Spectral analysis of molecular dynamics simulations on PDZ: MD sectors

“…All that is actually required for allosterism in proteins is an effector ligand binding which perturbs the free energy landscape such that the activity at a distal functional site is modulated. While one or more pathways may be involved, this is not unequivocally established, and allosterism may be a collective property of amino acid residues, ie an energy landscape model (Thayer, Galganov, & Stein, 2017). The task of identifying the composition of cooperative networks in proteins in general is a formidable task, and we do not presume to have solved this problem.…”

“…Some in the field also hold to the idea that allosteric communication is a collective property of the energy landscape of a protein, and thus distinct pathways of changes is not necessarily the way to look at the problem. Thayer and coworkers have estimated the plausibility of multiple means of allosteric communication within proteins from lattice models with PDZ as an example (Thayer, Galganov, & Stein, 2017).…”

Network Analysis of Molecular Dynamics Sectors in the p53 Protein

“…1 It remains to be proven, however, that such a sector conclusively identifies a cooperative network. 8 With these considerations in mind, we have recently developed two methods based on MD simulations to inform studies of allosteric proteins. MD sectors, like SCA sectors, yields a network of covarying residues, with a focus on motional covariance.…”

“…The Thayer lab has previously looked at the presence of contiguous pathways within protein systems, including p53. 8 Checking for the presence of contiguous pathways within protein sectors would be a logical addition to our network analysis techniques. Using Euclidean distance measures as edge-weights, we could visualize sector pathways and offer another scheme for constructing networks.…”

“…8 shows the percentage of edges remaining in each SHMC; to get this percentage for the NMDS SHMC, for example, we did the following calculation:…”