Ensemble origins and distance-dependence of long-range mutational effects in proteins

Mutational effects in globular proteins exhibit an exponential-like decreasing dependence on distance from the mutated site, suggestive of long-range modulation of structural-thermodynamic features. Here, we extract the physical origins of this pattern by employing a statistical-mechanical model to construct conformational ensembles of three archetypal proteins. Through large-scale in silico alanine-scanning mutagenesis, we show that inter-residue differential coupling free energies, which are characteristic ensemble thermodynamic properties, follow a similar exponential distance dependence with the effects felt until ∼15-20 Å from the mutated site. From the perspective of an ensemble-averaged structure, this feature arises via long-range reorganization of the interaction network on mutations which is more significant for charged residues compared to hydrophobic residues. Our work highlights how subtle alterations in the microscopic distribution of states manifest as a macroscopic distance dependence, the physical origins of mutation-induced dynamic allostery, and the necessity to consider the global intra-protein interaction network to understand mutational outcomes.