Energy Suppression Effect In Protein Folding: A Comparative Study Of Homologous Protein Transition State

Protein folding is listed as an important yet unsolved problem of 21st century biophysics and the central dogma of molecular biology. With deeper understanding of the protein folding mechanism during recent years, researchers realized that, rather than the common topological factors, energetic frustration and topological frustration might be two determining factors in exploring protein folding mechanism. Therefore, it becomes an increasingly interest task to quantitate the effects of these frustrations in shaping the protein folding. What the effects of energetic frustration in protein folding given distinct folding environments? To attack these problems, here in this thesis we designed a particular type of energetic frustration by introducing the non-native hydrophobic interactions and explored their roles in protein folding. Two set of proteins had been examined in this study:(1) five homologous proteins of Im9 family, which share nearly identical tertiary structures except sequential mutations at some non-native hydrophobic residues, and (2) four proteins of Im7 family, which all have nearly identical sequences except a missing of a couple of residues at C/N termini and but show certain difference in tertiary structures. The energetic frustrations are switched on after adding non-native hydrophobic interactions to the system as a revision of the simplest Go-like model and a new temperature-varying method was developed to facilitate the protein folding simulation. The φ-value analysis method was used to qualify the folding status of each amino acid in the transition state ensemble (TSE). Our calculations showed that the probability distribution of protein conformations in TSE can be perturbed at a different level by the energetic frustrations, depending on where these frustrations occur:the more closer to the centers of the native interaction network the larger the frustration can affect the protein folding; Another larger perturbation might be brought by frustrations introduced at random coil where its native-contacts is weak.