Folding simulations of small proteins Original Research Article

Understanding how a protein folds is a long-standing challenge in modern science. We have used an optimized atomistic model (united-residue force field) to simulate folding of small proteins of various structures: HP-36 (α protein), protein A (β), 1fsd (α+β), and betanova (β). Extensive Monte Carlo folding simulations (ten independent runs with 109 Monte Carlo steps at a temperature) starting from non-native conformations are carried out for each protein. In all cases, proteins fold into their native-like conformations at appropriate temperatures, and glassy transitions occur at low temperatures. To investigate early folding trajectories, 200 independent runs with 106 Monte Carlo steps are also performed at a fixed temperature for a protein. There are a variety of possible pathways during non-equilibrium early processes (fast process, ∼104 Monte Carlo steps). Finally, these pathways converge to the point unique for each protein. The convergence point of the early folding pathways can be determined only by direct folding simulations. The free energy surface, an equilibrium thermodynamic property, dictates the rest of the folding (slow process, ∼108 Monte Carlo steps).