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The folding energy landscape of Cytochrome c : theoretical and experimental investigations

  • Author(s): Weinkam, Patrick
  • et al.
Abstract

The folding energy landscape of cytochrome c is complicated by a large, covalently bound heme cofactor. The heme significantly stabilizes the native structure by providing a hydrophobic core and two ligation sites for a histidine and a methionine. Other residues or solvent molecules can compete for the heme ligation sites thereby affecting the protein's stability and folding mechanism. The relative stability of the heme ligands has a large effect on the folding and the dynamics of cytochrome c and is sensitive to the solvent conditions as well as the heme redox state. With the added complexity of the heme, some may think that cytochrome c is unique and has a folding mechanism that is unrelated to single domain proteins without cofactors. We will see however that the general principles used to describe the folding energy landscape are sufficient to describe the folding of cytochrome c. Models based on energy landscape ideas can predict behavior consistent with many experimental results. The most simple structure-based model, in which the energetics are based on information in the native fold, successfully predicts the sequential ordering of protein substructures. Changing the solvent conditions by varying pH, salt concentration, or by adding denaturant will destabilize the protein and perturb the energy landscape. By including nonnative effects into structure-based models, we can determine what features of the energy landscape are important in partially unfolded and denatured ensembles

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