All-atom folding simulations of the villin headpiece from stochastically selected coarse-grained structures

We discuss the application of a novel efficient protocol for the numerical simulation of the folding dynamics of single domain proteins from the only knowledge of primary sequence. Our approach is based on the combination of a Monte Carlo (MC) coarse-grained evolution followed by all-atom molecular dynamics (MD) simulations in explicit solvent. The coarse-grained model simplifies the protein's energy landscape and allows it to evolve rapidly toward viable starting conformations for MD. A general fine-graining algorithm is then used to reconstruct the full atomic detail of the protein. All atom MD simulations in explicit water are then employed to investigate the protein's conformational evolution toward the native state. We discuss the application of this novel approach to the Villin headpiece, a widely studied test system for folding studies, for which we obtain and maintain an RMS deviation from the NMR structure of 2.4 Angstrom for the core region and 3.7 Angstrom for the whole protein. Finally, the analysis of the MC-MD trajectories provides valuable insight into important aspects of the folding process with regards to the appearance and docking of locally secondary structure elements.