Folding of Top7 in unbiased all‐atom Monte Carlo simulations

For computational studies of protein folding, proteins with both helical and β‐sheet secondary structure elements are very challenging, as they expose subtle biases of the physical models. Here, we present reproducible folding of a 92 residue α/β protein (residues 3–94 of Top7, PDB ID: 1QYS) in computer simulations starting from random initial conformations using a transferable physical model which has been previously shown to describe the folding and thermodynamic properties of about 20 other smaller proteins of different folds. Top7 is a de novo designed protein with two α‐helices and a five stranded β‐sheet. Experimentally, it is known to be unusually stable for its size, and its folding transition distinctly deviates from the two‐state behavior commonly seen in natural single domain proteins. In our all‐atom implicit solvent parallel tempering Monte Carlo simulations, Top7 shows a rapid transition to a group of states with high native‐like secondary structure, and a much slower subsequent transition to the native state with a root mean square deviation of about 3.5 Å from the experimentally determined structure. Consistent with experiments, we find Top7 to be thermally extremely stable, although the simulations also find a large number of very stable non‐native states with high native‐like secondary structure. Proteins 2013; 81:1446–1456. © 2013 Wiley Periodicals, Inc.