Modeling of protein conformational changes with Rosetta guided by limited experimental data

ABSTRACT Conformational changes are an essential component of functional cycles of many proteins such as transporters or receptors. Despite their importance, the characterization of functionally-relevant structural intermediates is often a hard task for both experimental and computational methods. This limitation can be at least partially relieved by integrating experimental data within computational approaches. Such integrative structural biology strategies can yield an ensemble of models consistent with experimental data. While the macromolecular modeling suite Rosetta has been extensively used to predict protein structures de novo using various types of experimental data, an all-purpose conformational change modeling approach has been absent from this suite. Here, we introduce and benchmark ConfChangeMover (CCM), a new Rosetta Mover tailored to model conformational changes in proteins using sparse experimental data. CCM is able to rotate and translate secondary structural elements and modify their backbone dihedral angles in regions of interest. We benchmarked CCM on soluble and membrane proteins with sparse experimental double electron-electron resonance (DEER) restraints and simulated Cα - Cα distance restraints, respectively. In both benchmarks, CCM outperformed state-of-the-art Rosetta methods, showing that it can model a diverse array of conformational changes. In addition, the Rosetta framework allows a wide variety of experimental data to be integrated with CCM, thus extending its capability beyond DEER restraints. Thus, our method will contribute to the biophysical characterization of protein dynamics.