Model Study Of Protein Folding And Its Misfolding Diseases

Due to the complexity of protein folding mechanism, simplified models are widely used to study the essential and general properties of protein folding up to date. In this thesis, started with a brief overview of the current process of protein folding problem (Chapter 1); in Chapter 2, an introduction of the fundamentals of proteins and methods for protein structure prediction is given; then from Chapter 3 to 5, our research works, studied with the simple lattice models and exhaustive enumeration, are presented.In Chapter 3, we study the medium effects on the selection of sequences in protein folding. The medium effects are studied by taking account of the surface potential in a simple HP-lattice model. Our numerical calculation exhibits that the surface potential enhances the average energy gap for the highly designable structures. We obtained that the energy gap of the sequences with larger energy gap will mostly increase when the sequence is placed in medium. The linear increment of the largest average energy gap caused by the medium has a critical value for the parameter of the surface potential, which means that a most stable structure may be no longer the most stable one if the medium parameters changed. Our result shows that the sequences and structures selected by nature become more stable in proper medium and the nature may take different structures as the favorite structure in different mediums.In Chapter 4, we study the prion-like folding behavior in aggregated pro-teins. The prion-like folding behavior of a multimer, consisted of 27 individual model proteins, is studied with simple lattice model. By exhaustive enumer-ation, we get the prion-like behavior of protein folding. Individual proteins remaining stable in the isolated native state may change their conformations when they aggregate. We observe the change of the folding properties as the interfacial interaction strength changes, and find that the strength must be strong enough before the propagation of the most stable structures happens. Our result is in support of the' protein-only' hypothesis of prion diseases and consistent with some experimental observations that different environments likely influence the prion's ability to misfold and aggregate.In Chapter 5, the protein folding properties under the effect of secondary structural elements are investigated. We study the effect of secondary struc-tural elements by considering much lower pair contact energy in secondary structure like elements with HP lattice model. We observed the emergence of some structures which have both large average energy gap and high des-ignability. The kinetic study indicates that these structures are more kineti-cally reachable. These structures also possess much more secondary structure like elements. Our result indicates that the secondary structure may promote the selection of a few structures favorite by proteins.Finally, we analyze the symmetries of the maximally compact structures in cubic shape to pick out the structures unrelated by symmetries in appendix. We get the 51704 structures which are used in the calculation.