Abstract
<jats:p> Allosteric communication in proteins is commonly quantified as a directed or undirected coupling between residues, but such descriptors mix distinct modes of signalling into a single pattern. Here we treat the net transfer entropy flux from a dynamic Gaussian network(dGNM) model as an edge flow on the residue contact graph and apply the combinatorial Hodge decomposition, which dissects the flow orthogonally into a gradient (global source—to—sink hierarchy), a curl (local three—clique circulation) and a harmonic (cavity—scale circulation) component. Applied to the wild—type KRAS and ten oncogenic KRAS variants spanning the principal GTPase—cycle mechanism classes, partial—hydrolysis position—12 (G12D, G12C, G12S), GAP—occluding position—12 (G12V, G12R), catalytic switch II (Q61R, Q61H), fast—cycling (G13D, A146T) and a combined steric and catalytic double mutant (G12D/Q61H), on a side—chain—centroid contact network, the decomposition shows that the transfer entropy flux is overwhelmingly hierarchical: the gradient term carries 97.5—98.4% of the flux in every variant (permutation p = 0.002), and the recovered scalar potential is strongly anti—correlated with each residue's net outgoing transfer entropy (Spearman ρ ≈ −0.92 to −0.95). The hierarchy is conserved in magnitude but relocated by mutations: the dominant information sources move from the C terminal α <jats:sub>5/</jats:sub> hypervariable region in wild type into the nucleotide—processing core, the switch I/II machinery and the α <jats:sub>4/</jats:sub> distal lobe in a way that tracks the GTPase—cycle mechanism of the substitution, while the sinks remain fixed. The method provides a parameter—free, residue—level readout of how mutations of different mechanism reposition the source of allosteric signalling in KRAS. </jats:p>