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A Simple Model of Chaperonin-Mediated Protein Folding Hue Sun Chan and Ken A

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A Simple Model of Chaperonin-Mediated Protein Folding Hue Sun Chan and Ken A PROTEINS Structure, Function, and Genetics 24345-351 (1996) A Simple Model of Chaperonin-Mediated Protein Folding Hue Sun Chan and Ken A. Dill Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143-1204 ABSTRACT Chaperonins are oligomeric shape, with enough room in the center to hold a proteins that help other proteins fold. They act, compact collapsed protein. The inner walls of the according to the “Anfinsen cage” or “box of in- doughnut are hydrophobic. finite dilution” model, to provide private space, Experiments of Martin et al.14 suggested that protected from aggregation, where a protein “globular proteins may generally be sequestered can fold. Recent evidence indicates, however, during folding at the surface of a chaperonin-type that proteins are often ejected from the GroEL machinery.”14 This is sometimes referred to as the chaperonin in nonnative conformations, and “Anfinsen cage”15 or “box of infinte dil~tion”’~,’~ repeated cycles of binding and ejection are model, in which the main role of the chaperonin is to needed for successful folding. Some experimen- protect the folding protein from aggregation. An al- tal evidence suggests that GroEL chaperonins ternative mechanism to this “caging” process was can act as folding “catalysts” in an ATP-depen- later proposed by Burston et a1.,6 in which the chap- dent manner even when no aggregation takes eronin plays a more active role. According to this place. This implies that chaperonins must hypothesis, the energy provided by adenosine somehow recognize the kinetically trapped in- triphosphate (ATP) hydrolysis is used to disrupt in- termediate states of a protein. A central puzzle correct interactions in the kinetically trapped “mis- is how a chaperonin can catalyze the folding folded protein, allowing it to escape. This picture reaction of a broad spectrum of different pro- has gained support from more recent experi- teins. We propose a physical mechanism by ment~.~,~-’’Here we use a lattice model to study the which chaperonins can flatten the energy bar- energy barriers to protein folding in the presence of riers to folding in a nonspecific way. Using a chaperonins. lattice model, we illustrate how a chaperonin Studies of the folding kinetics of lattice model pro- could provide a sticky surface that helps pull teins indicate that some proteins can fall into low- apart an incorrectly folded protein so it can try energy kinetic traps as they fold.’’-’’ The trapped again to fold. Depending on the relative sizes of conformations are compact and hydrophobically the protein and the chaperonin cavity, folding clustered, and the subsequent slow steps in folding can proceed both inside and outside the chap- involve climbing up an energy hill out of the traps eronin. Consistent with experiments, we find by breaking noncovalent bonds in a sort of “breath- that the folding rate and amount of native pro- ing” step by which the chain expands to reach its tein can be considerably enhanced, or some- folding transition states. The nonspecific act of pull- times reduced, depending on the amino acid se- ing apart hydrophobic contacts can bring the protein quence, the chaperonin size, and the binding to a higher vista on the energy landscape, where it and ejection rates from the chaperonin. can try again to fold. We propose that the hydropho- 0 1996 Wiley-Liss, Inc. bic interiors of chaperonins may simply provide a hydrophobic surface that competes with intrachain Key words: energy landscape, kinetic traps, hydrophobic collapse and helps to pull apart com- hydrophobic interaction, multiple pact chain conformations. ATP is envisioned to pro- folding pathways, chaperone ac- vide the energy to unstick the protein from the chap- tion, lattice models eronin and release it to the exterior. In this way, the protein is given a series of opportunities to attempt INTRODUCTION folding inside and outside the chaperonin. Molecular chaperones may act by various mecha- nism~.’-~Hsp7O-family chaperones appear to pre- vent protein aggregation during folding.’-5 Here we consider the hsp60-family chaperonins, which can also act as folding catalysts,5-” in some cases even Received August 15, 1995; revision accepted October 13, when there appears to be no significant aggrega- 1995. Address reprint requests to Hue Sun Chan, Department of ti~n.~,’’The structure of the E. coli chaperonin Pharmaceutical Chemistry, Box 1204, University of Califor- GroEL is now It has a double-doughnut nia, San Francisco, CA 94143-1204. 0 1996 WILEY-LISS, INC. 346 H.S. CHAN AND K.A. DILL HP LATTICE MODEL antee that ejection and recollapse will necessarily lead to the correct native state. In general, the We model a folding protein using the two-dimen- ejected chains are not necessarily “committed” to sional (2D) HP lattice m~del.’~.~~Simple lattice the native state, but some fraction of them will fold models have been useful for exploring principles of to the native state via “throughway paths,”18*20i.e., protein folding and addressing problems of confor- along smooth funnel-like downhill energetic routes. mational changes that are too large to be treated by Others will fall into new kinetic traps1’aZ0 and the more microscopic model^.^,'^-^^ Here a protein is binding-ejection cycle is represented as a short chain of a specific sequence of The chaperonin thus acts through a general mech- two types of monomers, hydrophobic (H) and polar anism of barrier flattening by providing alternate (PI, for which configurations are explored by ex- folding pathways, or, in the terminology of M.J. haustive enumeration on 2D square lattices. We Todd, G.H. Lorimer, and D. Thir~malai,’~an “iter- consider only HP sequences that fold to unique na- ative annealling” process. The model shows that the tive states. Contacts between nonpolar units (HH chaperonin does not merely reduce barrier heights, contacts) are favorable by an energy E < 0. Despite as catalysts reduce transition state barriers, rather the obvious simplifications, such models have been the chaperonin completely changes a significant shown to resemble real proteins in their collapse part of the energy landscape, the part corresponding transitions, development of secondary and tertiary to compact conformations. The landscape of the com- structure, mutational properties, and folding kinet- plex, chaperonin plus protein, bears no simple rela- ic~.~~The top section in Figure 1shows a kinetically tion to the landscape of the protein alone. The chap- trapped configuration, B, followed by its transition eronin acts by iterative ejection of the proteins, but states a, b, c and the corresponding part of its “en- the distribution of conformations ejected from the ergy landscape,” on its way to the native state N. chaperonin is in general different from that of the We model the chaperonin as two hydrophobic sur- initial denatured conformations in refolding experi- faces separated by c lattice sites, so c is related to the ments. Therefore, the probability that the ejected radius of the doughnut hole. Only chain conforma- protein folds along throughway paths could be dif- tions that can fit into a c x c box can bind the chap- ferent from the probability + of throughway folding eronin. Figure 1 shows how the chaperonin flattens of the unchaperoned protein. It follows that if + is the energy barriers. The energies are lowered for the the yield of an unchaperoned folding experiment, conformations that are otherwise high-energy tran- the additional yield measured after one cycle of sitional states for the isolated protein along path- chaperonin action could be different from +(l - 4). ways of escape from the trap. The top of Figure 1 The bottom of Figure 1 shows a folding path of a shows that, in the absence of the chaperonin, step- chain that undergoes two cycles through a chapero- ping from the trap to the transition state involves nin before it reaches the native state. In all the HP breaking two HH contacts, up an energy hill of two sequences we studied, the chaperonin reduces the units. The middle of Figure 1shows ways the hydro- energy barrier for folding (although this is not suf- phobic residues of the protein can stick to the chap- ficient to imply acceleration of folding; see below). eronin instead of forming intrachain contacts. Thus Other theorie~~~~~-~~also propose that chaperonins the chaperonin pulls apart compact conformation^.^ create alternate folding pathways, but the present In some cases this can involve only small local struc- work is the first, as far as we know, to model the tural rearrangements, although extensive unfolding underlying physical mechanisms explicitly. inside the chaperonin is also possible in the present Can the protein fold inside the chaperonin? Not model. Sticking to the chaperonin involves downhill every conformational change inside the chaperonin energetic changes because the total energy is pro- necessarily involves further opening up of the pro- portional to the total number of hydrophobic con- tein. Hence some kinetic progress towards the na- tacts, either from intrachain interactions or from tive state is possible for some sequences. However, it proteidchaperonin interactions. The protein can un- can be difficult for a large protein to reach its native dergo further conformational changes inside the conformation inside a small chaperonin,14-17 for two chaperonin after initial binding (Fig. 1). Such reasons. First, in a small hydrophobic cavity, the changes need not involve large expansions. In this protein can adopt conformations for which the total model, ATP then pays the price of the main uphill energy is lower than the native state by reconfigur- energetic step, which involves unsticking the pro- ing to stick to the cavity walls. For a chaperonin of tein from the chaperonin and ejecting the protein. size c = 4, the most stable states of all the 13-mer Upon ejection, the protein is likely to have fewer HP sequences we studied are found when proteins intrachain HH contacts than when it entered.
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