PROTEIN-FOLDING MECHANISMS AND THE MULTIDIMENSIONAL FOLDING FUNNEL

An important idea that emerges from the energy landscape theory of pro tein folding is that subtle global features of the protein landscape c an profoundly affect the apparent mechanism of folding. The relationsh ip between various characteristic temperatures in the phase diagrams a nd landmarks in the folding funnel at fixed temperatures can be used t o classify different folding behaviors. The one-dimensional picture of a folding funnel classifies folding kinetics into four basic scenario s, depending on the relative location of the thermodynamic barrier and the glass transition as a function of a single-order parameter. Howev er, the folding mechanism may not always be quantitatively described b y a single-order parameter. Several other order parameters, such as de gree of secondary structure formation, collapse and topological order, are needed to establish the connection between minimalist models and proteins in the laboratory, In this article we describe a simple multi dimensional funnel based on two-order parameters that measure the degr ee of collapse and topological order. The appearance of several differ ent ''mechanisms'' is illustrated by analyzing lattice models with dif ferent potentials and sequences with different degrees of design. In m ost cases, the two-dimensional analysis leads to a classification of m echanisms totally in keeping with the one-dimensional scheme, but a to pologically distinct scenario of fast folding with traps also emerges, The nature of traps depends on the relative location of the glass tra nsition surface and the thermodynamic barrier in the multidimensional funnel. Proteins 32:136-158, 1998. (C) 1998 Wiley-Liss, Inc.