High resolution ensemble description of metamorphic and intrinsically disordered proteins using an efficient hybrid parallel tempering scheme

• Published in: Nature communications Vol. 12; no. 1; p. 958
• Main Authors: Appadurai, Rajeswari, Nagesh, Jayashree, Srivastava, Anand
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 11.02.2021; Nature Publishing Group UK; Nature Portfolio
• Subjects: Alanine; Entropy; Free energy; Intrinsically Disordered Proteins - chemistry; Molecular dynamics; Molecular Dynamics Simulation; NMR; Nuclear magnetic resonance; Nuclear Magnetic Resonance, Biomolecular; Peptide mapping; Peptides - chemistry; Protein Conformation; Proteins; Sampling; Scattering, Small Angle; Tempering; X-Ray Diffraction
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21105-7

Mapping free energy landscapes of complex multi-funneled metamorphic proteins and weakly-funneled intrinsically disordered proteins (IDPs) remains challenging. While rare-event sampling molecular dynamics simulations can be useful, they often need to either impose restraints or reweigh the generated data to match experiments. Here, we present a parallel-tempering method that takes advantage of accelerated water dynamics and allows efficient and accurate conformational sampling across a wide variety of proteins. We demonstrate the improved sampling efficiency by benchmarking against standard model systems such as alanine di-peptide, TRP-cage and β-hairpin. The method successfully scales to large metamorphic proteins such as RFA-H and to highly disordered IDPs such as Histatin-5. Across the diverse proteins, the calculated ensemble averages match well with the NMR, SAXS and other biophysical experiments without the need to reweigh. By allowing accurate sampling across different landscapes, the method opens doors for sampling free energy landscape of complex uncharted proteins.