Structural preference for changes in the direction of the Ca2+-induced transition: a study of the regulatory domain of skeletal troponin-C.

The determinants for specificity in the Ca(2+)-dependent response of the regulatory N-terminal domain of skeletal troponin-C are a combination of intrinsic and induced properties. We characterized computationally the intrinsic propensity of this domain for structural changes similar to those observed experimentally in the Ca(2+)-induced transition. The preference for such changes was assessed by comparing the structural effect of the harmonic and quasiharmonic vibrations specific for each Ca(2+) occupancy with crystallographic data. Results show that only the Ca(2+)-saturated form of the protein features a slow vibrational motion preparatory for the transition. From the characteristics of this mode, we identified a molecular mechanism for transition, by which residues 42-51 of helix B and of the adjacent linker move toward helices (A, D), and bind to the surface used by the protein to interact with troponin-I. By obstructing the access of the target to hydrophobic residues important in the formation of the complex, helix B and the adjacent linker act as an autoinhibitory structural element. Specific properties of the methionines at the interaction surface were found to favor the binding of the autoinhibitory region. Located over hydrophobic residues critical for binding, the methionines are easily displaceable to increase the accessibility of these residues to molecular encounter.