PROTEINS Structure, Function, and Genetics 26:271-287 (1996) On the Origin of the Cooperativity of Protein Folding: Implications From Model Simulations

ABSTRACT There is considerable experi-mental evidence that the cooperativity of pro-tein folding resides in the transition from the molten globule to the native state. The objective of this study is to examine whether simplified models can reproduce this cooperativity and if so, to identify its origin. In particular, the ther-modynamics of the conformational transition of a previously designed sequence (A. Kolinski, W. Galazka, and J. Skolnick, J. Chem. Phys. 103: 1028610297, 19951, which adopts a very stable Greek-key p-barrel fold has been investigated using the entropy Monte Carlo sampling (ESMC) technique of Hao and Scheraga (M.-H. Hao and H.A. Scheraga, J. Phys. Chem. 98: 98824883,1994). Here, in addition to the origi-nal potential, which includes one body and pair interactions between side chains, the force field has been supplemented by two types of multi-body potentials describing side chain interac-tions. These potentials facilitate the proteinlike pattern of side chain packing and consequently increase the cooperativity of the folding pro-cess. Those models that include an explicit co-operative side chain packing term exhibit a well-defined all-or-none transition from a dena-tured, random coil state to a high-density, well-defined, nativelike low-energy state. By con-trast, models lacking such a term exhibit a conformational transition that is essentially continuous. Finally, an examination of the con-formations at the free-energy barrier between the native and denatured states reveals that they contain a substantial amount of native-state secondary structure, about 50 % of the na-tive contacts, and have an average root mean square radius of gyration that is about 15% larger than native. o 1996 Wiley-Liss, hc. Key words: protein folding, protein thermody-namics, entropy sampling Monte Carlo, reduced protein models, folding intermediate