Toward a Theory on the Stability of Protein Folding: Challenges for Folding Models

Abstract: We adopt the point of view that analysis of the stability of the protein folding process is central to understanding the underlying physics of folding. Stability of the folding process means that many perturbations do not disrupt the progress from the random coil to the native state. In this paper we explore the stability of folding using established methods from physics and mathematics. Our result is a preliminary theory of the physics of folding. We suggest some tests of these ideas using folding simulations. We begin by supposing that folding events are related in some way to mechanical waves on the molecule. We adopt an analytical approach to the physics which was pioneered by M.V. Berry, (in another context), based upon mathematics developed mainly by R. Thom and V.I. Arnold. We find that the stability of the folding process can be understood in terms of structures known as caustics, which occur in many kinds of wave phenomena. The picture that emerges is that natural selection has given us a set of protein molecules which have mechanical waves that propagate according to several mathematically specific restrictions. Successful simulations of folding can be used to test and constrain these wave motions. With some additional assumptions the theory explains or is consistent with a number of experimental facts about folding. We emphasize that this wave-based approach is fundamentally different from energy-based approaches.