Conformational propagation with prion-like characteristics in a simple model of protein folding

Protein refolding/misfolding to an alternative form plays an aetiologic rol e in many diseases in humans, including Alzheimer's disease, the systemic a myloidoses, and the prion diseases. Here we have discovered that such refol ding can occur readily for a simple lattice model of proteins in a propagat able manner without designing for any particular alternative native state. The model uses a simple contact energy function for interactions between re sidues and does not consider the peculiarities of polypeptide geometry. In this model, under conditions where the normal (N) native state is marginall y stable or unstable, two chains refold from the N native state to an alter native multimeric energetic minimum comprising a single refolded conformati on that can then propagate itself to other protein chains. The only require ment for efficient propagation is that a two-faced mode of packing must be in the ground state as a dimer (a higher-energy state for this packings lea ds to less efficient propagation). For random sequences, these ground-state dimeric configurations tend to have more beta -sheet-like extended structu re than almost any other sort of dimeric ground-state assembly. This implie s that propagating states (such as for prions) are beta -sheet rich because the only likely propagating forms are beta -sheet rich. We examine the det ails of our simulations to see to what extent the observed propel-ties of p rion propagation can be predicted by a simple protein folding model. The fo rmation of the alternative state in the present model shows several distinc t features of amyloidogenesis and of prion propagation. For example, an ana log of the phenomenon of conformationally distinct strains in prions is obs erved. We find a parallel between 'glassy' behavior in liquids and the form ation of a propagatable state in proteins. This is the first report of simu lation of conformational propagation using any heteropolymer model. The res ults imply that some (but not most) small protein sequences must maintain a sequence signal that resists refolding to propagatable alternative native states and that the ability to form such states is not limited to polypepti des (or reliant on regular hydrogen bonding per se) but can occur for other protein-like heteropolymers.