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Probing Possible Downhill Folding: Native Contact Topology Likely Places a Significant Constraint on the Folding Cooperativity of Proteins with ∼40 Residues

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Probing Possible Downhill Folding: Native Contact Topology Likely Places a Significant Constraint on the Folding Cooperativity of Proteins with ∼40 Residues doi:10.1016/j.jmb.2008.09.023 J. Mol. Biol. (2008) 384, 512–530 Available online at www.sciencedirect.com Probing Possible Downhill Folding: Native Contact Topology Likely Places a Significant Constraint on the Folding Cooperativity of Proteins with ∼40 Residues Artem Badasyan, Zhirong Liu and Hue Sun Chan⁎ Department of Biochemistry Experiments point to appreciable variations in folding cooperativity among and Department of Molecular natural proteins with approximately 40 residues, indicating that the Genetics, Faculty of Medicine, behaviors of these proteins are valuable for delineating the contributing University of Toronto, Toronto, factors to cooperative folding. To explore the role of native topology in a Ontario, Canada M5S 1A8 protein's propensity to fold cooperatively and how native topology might constrain the degree of cooperativity achievable by a given set of physical Received 16 July 2008; interactions, we compared folding/unfolding kinetics simulated using received in revised form α three classes of native–centric C chain models with different interaction 6 September 2008; schemes. The approach was applied to two homologous 45-residue accepted 10 September 2008 fragments from the peripheral subunit-binding domain family and a 39- Available online residue fragment of the N-terminal domain of ribosomal protein L9. Free- 17 September 2008 energy profiles as functions of native contact number were computed to assess the heights of thermodynamic barriers to folding. In addition, chevron plots of folding/unfolding rates were constructed as functions of native stability to facilitate comparison with available experimental data. Although common Gō-like models with pairwise Lennard-Jones-type interactions generally fold less cooperatively than real proteins, the rank ordering of cooperativity predicted by these models is consistent with experiment for the proteins investigated, showing increasing folding cooperativity with increasing nonlocality of a protein's native contacts. Models that account for water-expulsion (desolvation) barriers and models with many-body (nonadditive) interactions generally entail higher degrees of folding cooperativity indicated by more linear model chevron plots, but the rank ordering of cooperativity remains unchanged. A robust, experimentally valid rank ordering of model folding cooperativity independent of the multiple native–centric interaction schemes tested here argues that native topology places significant constraints on how coop- eratively a protein can fold. © 2008 Elsevier Ltd. All rights reserved. Keywords: contact order; chevron plots; Gō model; desolvation barriers; Edited by M. Levitt many-body interactions Introduction Behaviors of natural proteins are consequences of *Corresponding author. E-mail address: an interplay between physics and biology. The struc- [email protected]. tural and dynamic properties of natural proteins are Present address: Z. Liu, College of Chemistry and dictated by physical forces acting in accordance with Molecular Engineering, Peking University, Beijing 100871, the proteins' amino acid sequences, which, in turn, China. are products of evolutionary selection for biological Abbreviations used: CI2, chymotrypsin inhibitor 2; functions. Naturally occurring proteins encompass NTL9, N-terminal domain of ribosomal protein L9; PDB, only a tiny fraction of all possible amino acid se- Protein Data Bank; PSBD, peripheral subunit-binding quences. Many natural protein properties—even domain; db, desolvation barriers; CO, contact order; RCO, generic trends—are atypical among random amino relative contact order. acid sequences (reviewed in Refs. 1,2). For many 0022-2836/$ - see front matter © 2008 Elsevier Ltd. All rights reserved. Native Topology and Protein Folding Cooperativity 513 natural globular proteins that fold and unfold population. As such, whether a protein folds in a reversibly, the kinetic accessibility of the folded state barrier-limited or downhill manner is intimately – suggests strongly that their energy landscapes3 6 are related to its folding cooperativity. The high degree funnel-like,3,6,7 constituting a special class of land- of cooperativity of many barrier-limited proteins is a scape shapes that does not necessarily apply to a physically remarkable property,49 suggesting that random amino acid sequence. Traditionally, folding cooperativity itself is a consequence of stringent – kinetics data of natural proteins were rationalized in biological selection.50 52 This recent finding from terms of activation processes over free-energy theory49,53,54 and experiment50 poses a serious con- barriers.8 Although the progress variables for free ceptual challenge since natural two-state proteins are energy were mostly unspecified in such a phenome- significantly more cooperative than coarse-grained nological approach, the method has provided many protein chain models55 constructed to embody useful insights. In this view, the folding/unfolding common intuitive notions of pairwise additive inter- kinetics of many single-domain proteins with ∼60– actions56 (e.g., the hydrophobic–polar interaction 100 residues is apparently limited by only a single scheme57,58). Apparently, only models that expli- barrier.9,10 This simple parametrization11 contrasts citly59,60 or tacitly61 (see comment on pp. 554–557 of markedly with that for the more complex folding Ref. 62 regarding the COREX algorithm61)involve kinetics of larger proteins, the interpretation of which nonadditive many-body effects63 are capable of often invoked transiently accumulating interme- producing cooperativity comparable to that observed diates12 and multiple barriers.13,14 experimentally.51,64,65 In this light, downhill folders In the energy landscape perspective, traditional may be amino acid sequences that did not undergo a barrier-limited folding is readily accounted for by rigorous selection for cooperativity or, for some funnel-like landscapes.15,16 Our horizon of possibili- reasons, their folded structures are not conducive to ties was broadened by the landscape perspective, cooperative folding. A comparison of the structural however, as it proposed that the folding of some and energetic differences between downhill and proteins may be downhill, or barrierless, along certain barrier-limited folding should, therefore, elucidate well-defined physical progress variables.3 In appar- both noncooperative and cooperative folding. ent confirmation of this prediction, recent experi- Studies of downhill folding so far has uncovered a mental studies suggested that the 37-residue tangible relationship between native topology and peripheral subunit binding domain from Escherichia folding cooperativity. In line with results calculated – coli's 2-oxoglutarate dehydrogenase multienzyme from Ising-like constructs66 68 that did not consider complex (BBL) undergoes downhill folding.17,18 explicit representations of the protein chain, recent Kinetic behaviors observed in earlier temperature investigations of explicit-chain models indicated jump experiments also indicated that the formation of that the contact pattern of native structure alone a compact globular intermediate from the cold- can yield substantial information about a protein's – denatured state of the 415-residue two-domain folding cooperativity. Using a continuum53,69 71 enzyme yeast phosphoglycerate kinase (PGK)19 likely native–centric Gō72 model for 16 proteins and a 16- proceeds in a downhill manner.20 Subsequent to the residue peptide, Zuo et al. found that folding BBL thermodynamic study,17 the cooperatively fold- cooperativity was well correlated with the number λ ing 80-residue 6–85 part of lambda repressor (wild of nonlocal contacts per residue in the protein's type)21 was found to be “tunable” by mutations native folded structure.36 Among the set of proteins towards downhill folding under a variety of stability they considered, which included some clearly two- – conditions.22 24 These discoveries sparked intense state proteins such as chymotrypsin inhibitor 2 interest. Notwithstanding the ongoing controversy (CI2), BBL was the least cooperative and barrierless regarding whether BBL is indeed a downhill folder,25–29 in the model.36 Using a similar modeling approach, λ investigations of BBL, 6–85 mutants, and other Knott and Chan compared four proteins, all with putative downhill-folding proteins have led to sig- ∼40 residues so as to minimize chain-length effects nificant experimental30–33 as well as theoretical34–42 that might otherwise obscure the impact of native advances (see Refs. 43,44 for reviews). More recently, topology on folding cooperativity.37 While recog- experimental folding data on a 62-residue version of nizing53,56 that the additive interactions used in their the gene product protein W from bacteriophage λ Gō model tend to underestimate the cooperativity of (gpW)45 provided evidence that gpW is yet another the proteins it seeks to model,37 they found clear example of a protein “poised toward downhill evidence that even such models could provide a folding”.46 crude prediction for the rank ordering of coopera- The phenomenon of downhill folding is a valuable tivity of real proteins. Specifically, their model for a window into general principles of protein energetics. 37-residue version of BBL [Protein Data Bank (PDB) It serves to bridge our understanding of conven- ID: 1BBL] was determined to be barrierless and, by tional barrier-limited folding with other paradigms comparison, much less cooperative than
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