Hydrophobic condensation and modular assembly model of protein folding
Despite several decades of intense study, protein folding problem remains elusive. In this paper, we review current knowledge and the prevailing thinking in the field, and summarize our work on the in vitro folding of a typical small globular protein, staphylococcal nuclease (SNase). Various thermodynamic and kinetic methods have been employed to determine the energetic and construct the energy landscape of folding. Data presented include, but not limit to, the identification of intermediate states, time courses of their spread and convergence on the landscape, and finally the often ignored step, the refinement of the overall conformation and hence the activation of the enzyme. Our goal is to have a complete perspective of the folding process starting from its initial unfolded state to the fully active native state. Analysis leads to these findings: the folding starts with the condensation of the hydrophobic side chains in different locales of the peptide chain. The newly forged hydrophobic environment facilitates formation of helix- and sheet-like frameworks at different domains. Consolidation and inter-docking of these frameworks or domains then stabilizes the overall conformation and refines the structure to activate the enzyme. Based on these observations we favor folding-by-parts and propose a modular assembly model for the in vitro folding of SNase.