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Aspartate carbamoyltransferase (ATCase) is a large dodecameric enzyme withsix active sites that exhibits allostery: its catalytic rate is modulated bythe binding of various substrates at distal points from the active sites. Arecently developed method, bond-to-bond propensity analysis, has proven capableof predicting allosteric sites in a wide range of proteins using anenergy-weighted atomistic graph obtained from the protein structure and givenknowledge only of the location of the active site. Bond-to-bond propensityestablishes if energy fluctuations at given bonds have significant effects onany other bond in the protein, by considering their propagation through theprotein graph. In this work, we use bond-to-bond propensity analysis to studydifferent aspects of ATCase activity using three different protein structuresand sources of fluctuations. First, we predict key residues and bonds involvedin the transition between inactive (T) and active (R) states of ATCase byanalysing allosteric substrate binding as a source of energy perturbations inthe protein graph. Our computational results also indicate that the effect ofmultiple allosteric binding is non linear: a switching effect is observed aftera particular number and arrangement of substrates is bound suggesting a form oflong range communication between the distantly arranged allosteric sites.Second, cooperativity is explored by considering a bisubstrate analogue as thesource of energy fluctuations at the active site, also leading to theidentification of highly significant residues to the T-R transition thatenhance cooperativity across active sites. Finally, the inactive (T) structureis shown to exhibit a strong, non linear communication between the allostericsites and the interface between catalytic subunits, rather than the activesite.

Allostery and cooperativity in multimeric proteins: bond-to-bond propensities in ATCase