Abstract
BackgroundEfficient communication between distant sites within a protein is essential for cooperative biological response. Although often associated with large allosteric movements, more subtle changes in protein dynamics can also induce long-range correlations. However, an appropriate formalism that directly relates protein structural dynamics to information exchange between functional sites is still lacking.ResultsHere we introduce a method to analyze protein dynamics within the framework of information theory and show that signal transduction within proteins can be considered as a particular instance of communication over a noisy channel. In particular, we analyze the conformational correlations between protein residues and apply the concept of mutual information to quantify information exchange. Mapping out changes of mutual information on the protein structure then allows visualizing how distal communication is achieved. We illustrate the approach by analyzing information transfer by the SH2 domain of Fyn tyrosine kinase, obtained from Monte Carlo dynamics simulations. Our analysis reveals that the Fyn SH2 domain forms a noisy communication channel that couples residues located in the phosphopeptide and specificity binding sites and a number of residues at the other side of the domain near the linkers that connect the SH2 domain to the SH3 and kinase domains. We find that for this particular domain, communication is affected by a series of contiguous residues that connect distal sites by crossing the core of the SH2 domain.ConclusionAs a result, our method provides a means to directly map the exchange of biological information on the structure of protein domains, making it clear how binding triggers conformational changes in the protein structure. As such it provides a structural road, next to the existing attempts at sequence level, to predict long-range interactions within protein structures.
Highlights
Efficient communication between distant sites within a protein is essential for cooperative biological response
Theoretical approaches have probed the relationship between protein structural dynamics and signal transduction, limited only by the combinatorial complexity associated with the conformational space
Together these studies show that (1) changes in protein dynamics can propagate through the protein structure thereby creating long range correlations between distal active sites [6,14], (2) only a fraction of residues in a protein structure participate in signal propagation [9,12], and (3) these intra-protein communication modes are generally conserved within protein families and even protein folds [4,7]
Summary
Efficient communication between distant sites within a protein is essential for cooperative biological response. Ranganathan and co-workers have mapped residues that participate in signal transduction in several important proteins by extracting evolutionary correlated mutations from multiple sequence alignments [7] Together these studies show that (1) changes in protein dynamics can propagate through the protein structure thereby creating long range correlations between distal active sites [6,14], (2) only a fraction of residues in a protein structure participate in signal propagation [9,12], and (3) these intra-protein communication modes are generally conserved within protein families and even protein folds [4,7]
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