Desolvation Barrier Effects Are a Likely Contributor to the Remarkable Diversity in the Folding Rates of Small Proteins

Ferguson, Allison; Liu, Zhongfan; Chan, Hue Sun

doi:10.1016/j.jmb.2009.04.011

Cited by 47 publications

(44 citation statements)

References 116 publications

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“…From the fitted curve to the black data points in Fig. 2B, the front factor F ≈ 4.6 × 10 −6 estimated by this relation is smaller, but it is within less than one order of magnitude from the F db ≈ 1.7 × 10 −5 value estimated previously for a similar class of explicit-chain protein models (39). A possible origin of this minor mismatch will be discussed below.…”

Section: Statistics Of Folding Trajectories Are Better Described By Csupporting

confidence: 51%

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Transition paths, diffusive processes, and preequilibria of protein folding

Zhang

Chan

2012

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

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Fundamental relationships between the thermodynamics and kinetics of protein folding were investigated using chain models of natural proteins with diverse folding rates by extensive comparisons between the distribution of conformations in thermodynamic equilibrium and the distribution of conformations sampled along folding trajectories. Consistent with theory and single-molecule experiment, duration of the folding transition paths exhibits only a weak correlation with overall folding time. Conformational distributions of folding trajectories near the overall thermodynamic folding/unfolding barrier show significant deviations from preequilibrium. These deviations, the distribution of transition path times, and the variation of mean transition path time for different proteins can all be rationalized by a diffusive process that we modeled using simple Monte Carlo algorithms with an effective coordinate-independent diffusion coefficient. Conformations in the initial stages of transition paths tend to form more nonlocal contacts than typical conformations with the same number of native contacts. This statistical bias, which is indicative of preferred folding pathways, should be amenable to future single-molecule measurements. We found that the preexponential factor defined in the transition state theory of folding varies from protein to protein and that this variation can be rationalized by our Monte Carlo diffusion model. Thus, protein folding physics is different in certain fundamental respects from the physics envisioned by a simple transition-state picture. Nonetheless, transition state theory can be a useful approximate predictor of cooperative folding speed, because the height of the overall folding barrier is apparently a proxy for related rate-determining physical properties. P rotein folding is an intriguing phenomenon at the interface of physics and biology. In the early days of folding kinetics studies, folding was formulated almost exclusively in terms of mass-action rate equations connecting the folded, unfolded, and possibly, one or a few intermediate states (1,2). With the advent of site-directed mutagenesis, the concept of free energy barriers from transition state theory (TST) (3) was introduced to interpret mutational data (4), and subsequently, it was adopted for the Φ-value analysis (5). Since the 1990s, the availability of more detailed experimental data (6), in conjunction with computational development of coarse-grained chain models, has led to an energy landscape picture of folding (7)(8)(9)(10)(11)(12)(13)(14)(15). This perspective emphasizes the diversity of microscopic folding trajectories, and it conceptualizes folding as a diffusive process (16-25) akin to the theory of Kramers (26).For two-state-like folding, the transition path (TP), i.e., the sequence of kinetic events that leads directly from the unfolded state to the folded state (27, 28), constitutes only a tiny fraction of a folding trajectory that spends most of the time diffusing, seemingly unproductively, in the vicinity of the ...

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Section: Statistics Of Folding Trajectories Are Better Described By Csupporting

confidence: 51%

“…Coarse-grained models (14, 38) were used for explicit-chain simulations. Like before (39,40), the fractional number of native contacts, Q, was used as a progress variable (41). Extensive statistics on folding path (FP), first passage time (FPT), TP, and t TP (Fig.…”

Section: Resultsmentioning

confidence: 99%

Transition paths, diffusive processes, and preequilibria of protein folding

Zhang

Chan

2012

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

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“…1B shows an overall barrier, indicating that folding is thermodynamically two-state. Because db enhances folding cooperativity (7,33,35), the overall barriers in the db þ hϕ S6 models are significantly higher than that in the Gō model. Consistent with experiment (14,15,28,29), these model results demonstrate a lack of two-state folding cooperativity for Top7 and two-state-like folding for S6.…”

Section: Native Topology Rationalizes Differences In Thermodynamic Fomentioning

confidence: 97%

“…We consider only the db þ hϕ models below because models that account for dbs are more realistic (6,7,33,35,37). In our analysis, the folded state and fully unfolded state were defined, respectively, by Q ≥ Q F and Q ≤ Q U .…”

Section: Native Topology Rationalizes Differences In Thermodynamic Fomentioning

confidence: 99%

“…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).…”

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confidence: 99%

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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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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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Kinetic consequences of native state optimization of surface‐exposed electrostatic interactions in the Fyn SH3 domain

et al. 2011

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Optimization of surface exposed charge-charge interactions in the native state has emerged as an effective means to enhance protein stability; but the effect of electrostatic interactions on the kinetics of protein folding is not well understood. To investigate the kinetic consequences of surface charge optimization, we characterized the folding kinetics of a Fyn SH3 domain variant containing five amino acid substitutions that was computationally designed to optimize surface charge-charge interactions. Our results demonstrate that this optimized Fyn SH3 domain is stabilized primarily through an eight-fold acceleration in the folding rate. Analyses of the constituent single amino acid substitutions indicate that the effects of optimization of charge-charge interactions on folding rate are additive. This is in contrast to the trend seen in folded state stability, and suggests that electrostatic interactions are less specific in the transition state compared to the folded state. Simulations of the transition state using a coarse-grained chain model show that native electrostatic contacts are weakly formed, thereby making the transition state conducive to nonspecific, or even nonnative, electrostatic interactions. Because folding from the unfolded state to the folding transition state for small proteins is accompanied by an increase in charge density, nonspecific electrostatic interactions, that is, generic charge density effects can have a significant contribution to the kinetics of protein folding. Thus, the interpretation of the effects of amino acid substitutions at surface charged positions may be complicated and consideration of only native-state interactions may fail to provide an adequate picture.

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Desolvation Barrier Effects Are a Likely Contributor to the Remarkable Diversity in the Folding Rates of Small Proteins

Cited by 47 publications

References 116 publications

Transition paths, diffusive processes, and preequilibria of protein folding

Transition paths, diffusive processes, and preequilibria of protein folding

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

Kinetic consequences of native state optimization of surface‐exposed electrostatic interactions in the Fyn SH3 domain

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