STATISTICAL-MECHANICS OF PROTEIN-FOLDING BY EXHAUSTIVE ENUMERATION

It is hard to construct theories for the folding of globular proteins because they are large and complicated molecules having enormous numbe rs of nonnative conformations and having native states that are compli cated to describe. Statistical mechanical theories of protein folding are constructed around major simplifying assumptions about the energy as a function of conformation and/or simplifications of the representa tion of the polypeptide chain, such as one point per residue on a cubi c lattice. It is not clear how the results of these theories are affec ted by their various simplifications. Here we take a very different si mplification approach where the chain is accurately represented and th e energy of each conformation is calculated by a not unreasonable empi rical function, However, the set of amino acid sequences and allowed c onformations is so restricted that it becomes computationally feasible to examine them all. Hence we are able to calculate melting curves fo r thermal denaturation as well as the detailed kinetic pathway of refo lding, Such calculations are based on a novel representation of the co nformations as points in an abstract la-dimensional Euclidean conforma tion space. Fast folding sequences have relatively high melting temper atures, native structures with relatively low energies, small kinetic barriers between local minima, and relatively many conformations in th e global energy minimum's watershed. In contrast to other folding theo ries, these models show no necessary relationship between fast folding and an overall funnel shape to the energy surface, or a large energy gap between the native and the lowest nonnative structure, or the dept h of the native energy minimum compared to the roughness of the energy landscape, (C) 1998 Wiley-Liss, Inc.