Probing the unfolded configurations of a $\beta$-hairpin using sketch-map

This work examines the conformational ensemble involved in $\beta$-hairpin folding by means of advanced molecular dynamics simulations and dimensionality reduction. A fully atomistic description of the protein and the surrounding solvent molecules is used and this complex energy landscape is sampled by means of parallel tempering metadynamics simulations. The ensemble of configurations explored is analysed using the recently proposed sketch-map algorithm. Further simulations allow us to probe how mutations affect the structures adopted by this protein. We find that many of the configurations adopted by a mutant are the same as those adopted by the wild type protein. Furthermore, certain mutations destabilize secondary structure containing configurations by preventing the formation of hydrogen bonds or by promoting the formation of new intramolecular contacts. Our analysis demonstrates that machine-learning techniques can be used to study the energy landscapes of complex molecules and that the visualizations that are generated in this way provide a natural basis for examining how the stabilities of particular configurations of the molecule are affected by factors such as temperature or structural mutations.
Comment: Pre-print of doi:10.1021/ct500950z, reproduced with permission from the ACS