Detalle de: Can Conformational Changes of Proteins Be Represented in Torsion Angle Space? A Study with Rescaled Ridge Regression

Torsion angles are the natural degrees of freedom of protein structures. The ability to determine torsional variations corresponding to observed changes in Cartesian coordinates is highly valuable, notably to investigate the mechanisms of functional conformational changes or to develop computational models of protein dynamics. This issue is far from trivial in practice since the impact of modifying one torsion angle strongly depends on all other angles, and the compounding effects of small variations in bond lengths and valence angles can completely disrupt a protein fold. We demonstrate that naive strategies, such as directly comparing torsion angles between structures without correcting for variations in bond lengths and valence angles or fitting torsional variations without a proper regularization scheme, fail at producing an adequate representation of conformational changes in internal coordinates. In contrast, rescaled ridge regression, a method recently introduced to regularize multidimensional regressions with correlated explanatory variables, is shown to consistently identify a minimal set of torsion angles variations that closely reproduce changes in Cartesian coordinates. This torsional representation of conformational changes is shown to be robust to the choice of experimental structures. It also provides a better agreement with theoretical models of protein dynamics than the Cartesian representation, regarding notably the predominance of low-frequency normal modes in functional motions and the presence, in predicted equilibrium dynamics, of hints of natural selection for specific functional motions. The software is available at https://github.com/ugobas/tnm .