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

Area of Science:

• Structural Biology
• Biophysics
• Computational Biology

Background:

• Protein conformational changes are crucial for biological function.
• Characterizing these dynamics often requires integrative structural biology approaches.
• Existing methods may have limitations in modeling diverse conformational changes.

Purpose of the Study:

• To introduce and benchmark ConfChangeMover (CCM), a novel method within the Rosetta suite.
• To enable modeling of protein conformational changes using sparse experimental data.
• To improve the characterization of protein dynamics.

Main Methods:

• ConfChangeMover (CCM) was developed and integrated into the Rosetta macromolecular modeling suite.
• CCM allows rotation and translation of secondary structural elements and modification of backbone dihedral angles.
• Benchmarking involved simulated Cα-Cα distance restraints for soluble proteins and experimental double electron-electron resonance (DEER) restraints for membrane proteins.

Main Results:

• CCM demonstrated superior performance compared to state-of-the-art Rosetta methods in both soluble and membrane protein benchmarks.
• The method successfully modeled a diverse range of protein conformational changes.
• CCM's integration within the Rosetta framework allows for the incorporation of various experimental data types beyond DEER restraints.

Conclusions:

• ConfChangeMover (CCM) is an effective new tool for modeling protein conformational changes.
• CCM enhances the capability of modeling protein dynamics using sparse experimental data.
• This method will advance the biophysical characterization of protein functional cycles.