Low-dimensional energetic landscape governing Ca2+ binding in troponin C.

Ca2+ binding regulates muscle contraction through coupled structural and dynamical mechanisms, yet a unified description of mutation-induced perturbations in binding energetics remains incomplete. Mutational effects on proteins are often high dimensional and difficult to interpret mechanistically. Here, we develop a physically interpretable low-dimensional reaction coordinate that captures coordination environment, electrostatic features, and dynamical coupling. Structural, electrostatic, and dynamical descriptors correlate with experimental binding free energies with Pearson coefficients of Rp = 0.83, 0.83, and 0.85, respectively. Integration of these domains improves agreement with experiment (Rp = 0.90), indicating substantial dimensional compression of the underlying descriptor space. This framework provides a physically grounded description of how mutations reshape Ca2+-binding energetics in a minimal EF-hand system.