Systematic Approach to Find the Global Minimum of Relaxation Dispersion Data for Protein-Induced B-Z Transition of DNA

Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersion spectroscopy is commonly used for quantifying conformational changes of protein in mu s-to-ms timescale transitions. To elucidate the dynamics and mechanism of protein binding, parameters implementing CPMG relaxation dispersion results must be appropriately determined. Building an analytical model for multi-state transitions is particularly complex. In this study, we developed a new global search algorithm that incorporates a random search approach combined with a field-dependent global parameterization method. The robust inter-dependence of the parameters carrying out the global search for individual residues (GSIR) or the global search for total residues (GSTR) provides information on the global minimum of the conformational transition process of the Z alpha domain of human ADAR1 (hZ alpha(ADAR1))-DNA complex. The global search results indicated that a alpha-helical segment of hZ alpha(ADAR1) provided the main contribution to the three-state conformational changes of a hZ alpha(ADAR1)-DNA complex with a slow B-Z exchange process. The two global exchange rate constants, k(ex) and k(ZB), were found to be 844 and 9.8 s(-1), respectively, in agreement with two regimes of residue-dependent chemical shift differences-the dominant oscillatory regime and semi-oscillatory regime. We anticipate that our global search approach will lead to the development of quantification methods for conformational changes not only in Z-DNA binding protein (ZBP) binding interactions but also in various protein binding processes.

Automated summary

A new global search algorithm was developed to determine the dynamics and mechanism of protein binding, revealing that the α-helical segment plays a key role in the three-state conformational changes of the hZα(ADAR1)-DNA complex, providing information on the global minimum of the conformational transition process.