Cooperativity in protein-folding kinetics.

Abstract

How does a protein find its native state without a globally exhaustive search? We propose the "HZ" (hydrophobic zipper) hypothesis: hydrophobic contacts act as constraints that bring other contacts into spatial proximity, which then further constrain and zip up the next contacts, etc.In contrast to helix-coil cooperativity, HZ-heteropolymer collapse cooperatvity is driven by nonlocal interactions, causes sheet and irregular conformations in addition to helices, leads to secondary structurs concurrentiy with early hydrophobic core formation, is much more sequence dependent than helixcoil processes, and involves compact intermediate states that have much secondary-but little tertiary-structure. Hydrophobic contacts in the 1992 Protein Data Bank have the type of "topologial localness" predicted by the hypothesis. The HZ paths for amino acid sequences that mimic crambin and bovine pancreatic trypsin inhibitor are quickly found by computer; the best configurations thus reached have single hydrophobic cores that are within about 3 kcal/mol of the global minimum. This hypothesis shows how proteins could find globally optimal states without exhautive search.What is the origin of cooperativity in protein folding? Some proteins fold reversibly (1, 2), independently of pathway (3-5), to a unique native state. These native states must be at the global minimum of free energy that is accessible on the experimental time scale. To guarantee that a computational strategy finds the global optimum requires a search time that scales exponentially with chain length (6, 7). However, Levinthal (8) and Wetlaufer (9) pointed out that proteins fold much too fast (by at least tens of orders of magnitude) to involve an exhaustive search. Hence, the kinetics/thermodynamics paradox: how can a protein find a globally optimal state without a globally exhaustive search? It follows that the folding problem is not so much a problem of exhaustive computational searching as it is the question of what is the physical basis of cooperativity by which proteins avoid exhaustive searching of conformational space. This view has led to important experiments on protein-folding mechanisms and pathways (10-23).The main paradigm for cooperativity in biopolymers is the helix-coil theory (24-27). "Cooperativity" describes how a globally optimal state can be found without a global search, hence cooperativity involves conformational choices that must be local in some sense. The nature of "localness" is at the heart of cooperativity. For helix-coil processes, the global minimum (the helix) is found by local processes by which each individual tetrapeptide in the sequence finds a hydrogen-bonded helical conformation; the partition function for the whole chain is a product of partition functions for individual helical units (24)(25)(26)(27). Such processes are local in two respects. (i) Monomers i andj that seek to form a helical hydrogen-bonding contact are "sequence-local" (S-local)-i.e., near neighbors in the sequence (j = i + 3 for a-helices,

The loop hypothesis: contribution of early formed specific non-local interactions to the determination of protein folding pathways

“…Using a cubic lattice simulation, Shakhnovich (Abkevich et al 1995) found that NLIs contribute to a faster rate of folding. However, the results of many other studies support the counterhypothesis that the folding mechanism is dominated by LIs, while the non-local ones provide non-specific stabilization of the compact conformers (Anfinsen and Scheraga 1975;Harrison and Durbin 1985;Wright et al 1988;Rooman et al 1992;Dill et al 1993;Weikl and Dill 2003) and nucleation (Wetlaufer 1973;Daggett and Fersht 2003;Kihara 2005) The question of whether the LIs or NLIs are more important or dominant in the initiation of folding, or for determination of the direction and rate of the folding transition remains open, and is the subject of the present review. Fig.…”

“…In these models, the NLIs are assumed to have smaller role and can be non-specific. In the zipping and assembly (ZA) mechanism suggested by Dill's group (Dill et al 1993), local structuring happens first at independent sites along the chain, then those structures either grow (zip) or coalescence (assemble) with other structures (Ozkan et al 2007;Dill et al 2008;Shell et al 2009). Dill argues that the ZA mechanism is a model for the physical pathways of protein folding.…”

The folding process of hen lysozyme: a perspective from the ‘new view’

“…The early collapse of the polypeptide chain is represented by the steep drop at the top of figure 4. That this is indicated to occur at relatively low values of Q reflects the fact that few native-like contacts may be needed for collapse to occur; the driving force is likely to be simply the burial of hydrophobic groups [6,36]. From this highly heterogeneous collapsed state, nativelike structure develops independently in the two structural domains, and hence intermediates are formed.…”

Addition of side chain interactions to modified Lifson‐Roig helix‐coil theory: Application to energetics of Phenylalanine‐Methionine interactions

“…Side chain interactions between two nonpolar bution to protein stability. Exclusion of water from hydrophobic surfaces is thought to occur early in the folding pathway (Dill et al, 1993), and there is evidence that hydrophobic clusters arise in denatured states (Neri et al, 1992;Shortle, 1993) and in folding intermediates (Martensson et al, 1993). A recent statistical study of protein crystal structures has revealed strong correlations for specific pairs of amino acids spaced i, i + 4 in a-helices; the strongest preferences are for salt bridges, Leu-Leu and Phe-Met (Klingler & Brutlag, 1995).…”