EXPLORING THE FOLDING FREE-ENERGY SURFACE OF A 3-HELIX BUNDLE PROTEIN

The multidimensional free energy surface for a small fast folding heli cal protein is explored based on first-principle calculations, The mod el represents the 46-residue segment from fragment B of staphylococcal protein A. The relationship between collapse and tertiary structure f ormation, and the order of collapse and secondary structure formation, are investigated. We find that the initial collapse process gives ris e to a transition state with about 30% of the native tertiary structur e and 50-70% of the native helix content, We also observe two distinct distributions of native helix in this collapsed state (R-g approximat e to 12 Angstrom, one with about 20% of the native helical hydrogen bo nds, the other with near 70%. The former corresponds to a local minimu m. The barrier from this metastable state to the native state is about 2 k(B)T. In the latter case, folding is essentially a downhill proces s involving topological assembly. In addition, the order of formation of secondary structure among the three helices is examined, We observe cooperative formation of the secondary structure in helix I and helix II, Secondary structure in helix III starts to form following the for mation of certain secondary structure in both helix I and helix II, Co mparisons of our results with those from theory and experiment are mad e.