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

Conformational changes are an essential component of functional cycles of many proteins, but their charac-terization often requires an integrative structural biology approach. Here, we introduce and benchmark ConfChangeMover (CCM), a new method built into the widely used macromolecular modeling suite Rosetta that is tailored to model conformational changes in proteins using sparse experimental data. CCM can 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 simulated Ca-Ca distance restraints and sparse experimental double electron-electron resonance (DEER) restraints, respectively. In both bench-marks, 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. This method will contribute to the biophysical characterization of protein dynamics.

Automated summary

Conformational changes are crucial for the functional cycles of proteins, and their study often requires an integrative approach. In this study, a new method called ConfChangeMover (CCM) was introduced and tested for modeling protein conformational changes using sparse experimental data. CCM outperformed state-of-the-art methods in two benchmarks, demonstrating its ability to model diverse conformational changes. Moreover, the integration of CCM with other experimental data using the Rosetta framework further expands its capability.