Topological and energetic factors: What determines the structural details of the transition state ensemble and "en-route" intermediates for protein folding? An investigation for small globular proteins

Recent experimental results suggest that the native fold, or topology, play s a primary role in determining the structure of the transition state ensem ble, at least for small, fast-folding proteins. To investigate the extent o f the topological control of the folding process, we studied the folding of simplified models of five small globular proteins constructed using a G (o ) over bar-like potential to retain the information about the native struct ures but drastically reduce the energetic frustration and energetic heterog eneity among residue-residue native interactions. By comparing the structur e of the transition state ensemble (experimentally determined by Phi-values ) and of the intermediates with those obtained using our models, we show th at these energetically unfrustrated models can reproduce the global experim entally known features of the transition state ensembles and "en-route" int ermediates, at least for the analyzed proteins. This result clearly indicat es that, as long as the protein sequence is sufficiently minimally frustrat ed, topology plays a central role in determining the folding mechanism. (C) 2000 Academic Press.