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

Badasyan, Artem; Liu, Zhirong; Chan, Hue Sun

doi:10.1016/j.jmb.2008.09.023

Cited by 40 publications

(92 citation statements)

References 129 publications

(211 reference statements)

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“…For instance, the negative correlation between native contact order and folding rate among small proteins (23) is consistent with predictions (18)(19)(20)24) that proteins with higher native topological complexity tend to have higher folding barriers and thus fold more cooperatively. Here we focus mainly on folding kinetics, which affords more accurate characterizations of folding cooperativity than thermodynamics alone.…”

supporting

confidence: 79%

“…A recent analysis suggested, however, that a deeper cause might be that the Top7 topology itself is not conducive to cooperative folding (16). This view is consistent with several model studies indicating that native topology can constrain folding cooperativity (17)(18)(19)(20). Thus, motivated by the same perspective that led to the considerations of a target structure's encodability (21) or designability (22), it is of interest to go a step further to assess a structure's designability for folding cooperativity.…”

supporting

confidence: 53%

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Competition between native topology and nonnative interactions in simple and complex folding kinetics of natural and designed proteins

Zhang

Chan²

2010

Proc. Natl. Acad. Sci. U.S.A.

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150

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We compared folding properties of designed protein Top7 and natural protein S6 by using coarse-grained chain models with a mainly native-centric construct that accounted also for nonnative hydrophobic interactions and desolvation barriers. Top7 and S6 have similar secondary structure elements and are approximately equal in length and hydrophobic composition. Yet their experimental folding kinetics were drastically different. Consistent with experiment, our simulated folding chevron arm for Top7 exhibited a severe rollover, whereas that for S6 was essentially linear, and Top7 model kinetic relaxation was multiphasic under strongly folding conditions. The peculiar behavior of Top7 was associated with several classes of kinetic traps in our model. Significantly, the amino acid residues participating in nonnative interactions in trapped conformations in our Top7 model overlapped with those deduced experimentally. These affirmations suggest that the simple ingredients of native topology plus sequence-dependent nonnative interactions are sufficient to account for some key features of protein folding kinetics. Notably, when nonnative interactions were absent in the model, Top7 chevron rollover was not correctly predicted. In contrast, nonnative interactions had little effect on the quasi linearity of the model folding chevron arm for S6. This intriguing distinction indicates that folding cooperativity is governed by a subtle interplay between the sequence-dependent driving forces for native topology and the locations of favorable nonnative interactions entailed by the same sequence. Constructed with a capability to mimic this interplay, our simple modeling approach should be useful in general for assessing a designed sequence's potential to fold cooperatively.T he study of protein folding is important not only for deciphering the folding process and how misfolding can occur. The principles developed in theoretical investigations of folding (1-3) have provided insights into a broad range of molecularrecognition phenomena and dynamic behaviors in biology. Recent examples include protein-protein interactions (4), function of biomolecular machines (5), effects of desolvation in selfassembly (6, 7), and switch-like properties in binding (8). Among naturally evolved proteins, many fold cooperatively in a twostate-like manner (9), which is a remarkable feat from the vantage point of polymer physics (10). Although not all natural proteins share this property (11), its commonality argues that folding cooperativity may serve crucial biological functions such as guarding against harmful aggregation (12).If cooperative folding can be a desirable trait under certain circumstances, a fundamental question arises: Can all folded globular structures attain a high degree of folding cooperativity? A revealing case is the designed protein Top7 (13), which folds to a de novo target structure that did not exist previously in the Protein Data Bank (PDB) but does so noncooperatively (14, 15). One possible reason for Top7's failure to fold coo...

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supporting

confidence: 79%

supporting

confidence: 53%

Competition between native topology and nonnative interactions in simple and complex folding kinetics of natural and designed proteins

Zhang

Chan²

2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

150

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“…Theoretical considerations indicate that the lack of two-state-like behaviour of Top7 is probably caused more fundamentally by its peculiar native structure, more so than the fact that it is an artificially designed protein that did not undergo natural selection [156]. Thus, native geometry or topology (the pattern of residue-residue contacts in the native structure) probably impose a physical constraint on the level of stability and folding cooperativity that natural or artificial selection can achieve [156,157]. In this connection, it has been shown using simple lattice protein models that not all protein structures are equally encodable [158] or designable [159 -161].…”

Section: Reconciling Evolutionary Selection For Stability With Marginmentioning

confidence: 99%

Biophysics of protein evolution and evolutionary protein biophysics

Sikosek

Chan

2014

J. R. Soc. Interface.

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224

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The study of molecular evolution at the level of protein-coding genes often entails comparing large datasets of sequences to infer their evolutionary relationships. Despite the importance of a protein's structure and conformational dynamics to its function and thus its fitness, common phylogenetic methods embody minimal biophysical knowledge of proteins. To underscore the biophysical constraints on natural selection, we survey effects of protein mutations, highlighting the physical basis for marginal stability of natural globular proteins and how requirement for kinetic stability and avoidance of misfolding and misinteractions might have affected protein evolution. The biophysical underpinnings of these effects have been addressed by models with an explicit coarse-grained spatial representation of the polypeptide chain. Sequence-structure mappings based on such models are powerful conceptual tools that rationalize mutational robustness, evolvability, epistasis, promiscuous function performed by 'hidden' conformational states, resolution of adaptive conflicts and conformational switches in the evolution from one protein fold to another. Recently, protein biophysics has been applied to derive more accurate evolutionary accounts of sequence data. Methods have also been developed to exploit sequence-based evolutionary information to predict biophysical behaviours of proteins. The success of these approaches demonstrates a deep synergy between the fields of protein biophysics and protein evolution.

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“…Although hydrophobic burial alone may be insufficient to yield cooperative folding behavior (60,61), a common presumption is that formation of a hydrophobic core is requisite for two-state folding behavior (11). Simulations and experiments have also stressed the importance of long-range contacts (62,63). Other factors include multibody energy terms (64), instability of isolated substructures, side-chain packing (11), desolvation (65), and the lack of stable, misfolded structures.…”

Section: Significancementioning

confidence: 99%

Perplexing cooperative folding and stability of a low-sequence complexity, polyproline 2 protein lacking a hydrophobic core

Gates

Baxa

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The burial of hydrophobic side chains in a protein core generally is thought to be the major ingredient for stable, cooperative folding. Here, we show that, for the snow flea antifreeze protein (sfAFP), stability and cooperativity can occur without a hydrophobic core, and without α-helices or β-sheets. sfAFP has low sequence complexity with 46% glycine and an interior filled only with backbone H-bonds between six polyproline 2 (PP2) helices. However, the protein folds in a kinetically two-state manner and is moderately stable at room temperature. We believe that a major part of the stability arises from the unusual match between residue-level PP2 dihedral angle bias in the unfolded state and PP2 helical structure in the native state. Additional stabilizing factors that compensate for the dearth of hydrophobic burial include shorter and stronger H-bonds, and increased entropy in the folded state. These results extend our understanding of the origins of cooperativity and stability in protein folding, including the balance between solvent and polypeptide chain entropies.protein folding | cooperativity | kinetics | PP2 | hydrogen bonding T he basis of protein-folding stability and cooperativity remains a topic of great interest (1, 2). Most studies have focused on proteins with hydrophobic cores containing α-helices and β-sheets. Here, we study the folding of snow flea antifreeze protein (sfAFP), a globular protein that lacks these features. The 81-residue protein has a novel fold that is distinct from other proteins (3-6), containing only polyproline 2 (PP2) helices and turns with a core filled with H-bonds and no hydrophobic groups (Fig. 1).The H-bond network between the PP2 helices (6), PP2 1-6 , requires close packing, which would be precluded by the presence of a C β atom. Thus, the PP2 helices are defined by glycine (Gly) repeats (GXX or GGX, where X is any other amino acid), which enable the hydrogen-bond network. As a consequence, the sfAFP molecule has a low-complexity glycine-rich sequence [37/81 Gly residues, or 46%; typical is 6, or 7% (7)]. The sfAFP core is well packed with essentially no interior void volumes, even when probed using a 0.5-Å radius sphere (8). sfAFP also contains two disulfide bonds, C1-C28 and C13-C43.Notably, no side chains are buried in sfAFP's core (2). All 12 hydrophobic side chains (V 4 , K 2 , and P 6 ) are surface exposed. Upon folding, sfAFP buries about 20 Å 2 ·res −1 of hydrophobic surface area compared with an average of 50 Å 2 ·res −1 for a set of 34 proteins of similar size (Fig. 2A). The difference equates to a decrease in stability of ∼1 or 1.4 kcal·mol −1 ·res −1 , assuming a surface tension coefficient of γ ∼ 34 or 47 cal·mol −1 ·Å −2 based on classical (9) or Flory-Huggins theory (10), respectively. Even the lower bound of 1 kcal·mol −1 ·res −1 represents a significant stability loss, and it is not obvious which energetic terms could compensate for the reduction in hydrophobic burial.Because hydrophobic burial is generally regarded as the basis of protein stability a...

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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

Cited by 40 publications

References 129 publications

Competition between native topology and nonnative interactions in simple and complex folding kinetics of natural and designed proteins

Competition between native topology and nonnative interactions in simple and complex folding kinetics of natural and designed proteins

Biophysics of protein evolution and evolutionary protein biophysics

Perplexing cooperative folding and stability of a low-sequence complexity, polyproline 2 protein lacking a hydrophobic core

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