How Well Evolved Is The Folding Code?

Abstract

Proteins are thought to fold on rugged energy landscapes, most proteins folding via kinetically trapped intermediates that accumulate as partially folded structures. Whilst such species may form essential stepping stones to the native state, others may allow access to misfolding pathways. Key to understanding the portioning between folding and misfolding, therefore, is to elucidate the structures of partially folded intermediates and to identify features of such species that favour correct folding or promote aberrant folding. Such information is not only of fundamental importance, but underpins our quest to elucidate the mechanism of chaperone action and the events that occur to tip the balance between folding and aggregation. In an attempt to gain high resolution information about the structure of intermediate species, we have used protein engineering, hydrogen exchange and chemical shift analysis, combined with restrained molecular dynamics simulations to derive a model for the structure of an intermediate formed during the folding of the four helical protein, Im7. More recently, we have used these techniques to determine the mechanism for intermediate formation, and hence the very earliest steps in folding wherein the native topology is formed. The data reveal an unusual ruggedness in the folding landscape of this simple protein that we suggest results from the evolutionary pressure to evolve new functions within this simple protein scaffold. In this lecture these results will be described and the influence of functional restraints in determining folding efficiency will be discussed.