Signal Propagation in Proteins and Relation to Equilibrium Fluctuations

Elastic network (EN) models have been widely used in recent years for describing protein dynamics, based on the premise that the motions naturally accessible to native structures are relevant to biological function. We posit that equilibrium motions also determine communication mechanisms inherent to the network architecture. To this end, we explore the stochastics of a discrete-time, discrete-state Markov process of information transfer across the network of residues. We measure the communication abilities of residue pairs in terms of hit and commute times, i.e., the number of steps it takes on an average to send and receive signals. Functionally active residues are found to possess enhanced communication propensities, evidenced by their short hit times. Furthermore, secondary structural elements emerge as efficient mediators of communication. The present findings provide us with insights on the topological basis of communication in proteins and design principles for efficient signal transduction. While hit/commute times are information-theoretic concepts, a central contribution of this work is to rigorously show that they have physical origins directly relevant to the equilibrium fluctuations of residues predicted by EN models.: In recent years, there has been a surge in the number of studies using network models for understanding biomolecular systems dynamics. Essentially, two different groups of studies have been performed, driven by two different communities. The first is based on molecular biophysics and statistical mechanical concepts. Normal mode analyses using elastic network models lie in this group. The second is based on information theory and spectral graph methods. The present study demonstrates for the first time that signal transduction events directly depend on the fluctuation dynamics of the biomolecular systems, thus establishing the bridge between the (newly proposed) information-theoretic and the (well-established) physically inspired approaches. We have applied the new approach to five different enzymes. Functionally active residues are shown to possess enhanced communication propensities. Furthermore, secondary structural elements emerge as efficient mediators of communication. These results provide us with important insights for protein design and mechanisms of allostery.