Theory of Kinetic Partitioning in Protein Folding (With Application to Prions)

Abstract

In this paper we study the phenomenon of kinetic partitioning when a polypeptide chain has two ground state conformations one of which is more kinetically reachable than the other. This question is relevant to understand the phenomenology of prions, proteins which exist in the cell in non-pathogenic $α$-helical conformation but under certain circumstances may transform into pathogenic $PrP^{Sc}$ state featuring increased $β$-sheet content. We designed sequences for lattice model proteins having two different conformations of equal energy corresponding to the global energy minimum. Folding simulations revealed that one of these conformations was indeed much more kinetically accessible than the other. We found that the number and strength of local contacts in the ground state conformation is the major factor which determines which conformation is reached faster: The greater the number of local contacts the more kinetically reachable a conformation is. We present simple statistical-mechanical arguments to explain these findings. The presented results are in a clear agreement with experimental data on prions and other proteins exhibiting kinetic partitioning.