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Allosteric regulation at distant sites is central to many cellular processes.In particular, allosteric sites in proteins are a major target to increase therange and selectivity of new drugs, and there is a need for methods capable ofidentifying intra-molecular signalling pathways leading to allosteric effects.Here, we use an atomistic graph-theoretical approach that exploits Markovtransients to extract such pathways and exemplify our results in an importantallosteric protein, caspase-1. Firstly, we use Markov Stability communitydetection to perform a multiscale analysis of the structure of caspase-1 whichreveals that the active conformation has a weaker, less compartmentalisedlarge-scale structure as compared to the inactive conformation, resulting ingreater intra-protein coherence and signal propagation. We also carry out afull computational point mutagenesis and identify that only a few residues arecritical to such structural coherence. Secondly, we characterise explicitly thetransients of random walks originating at the active site and predict thelocation of a known allosteric site in this protein quantifying thecontribution of individual bonds to the communication pathway between theactive and allosteric sites. Several of the bonds we find have been shownexperimentally to be functionally critical, but we also predict a number of asyet unidentified bonds which may contribute to the pathway. Our approach offersa computationally inexpensive method for the identification of allosteric sitesand communication pathways in proteins using a fully atomistic description.

Uncovering allosteric pathways in caspase-1 with Markov transient analysis and multiscale community detection