Capillarity-like growth of protein folding nuclei

Qi, Xianghong; Portman, John J.

doi:10.1073/pnas.0711527105

Cited by 10 publications

(8 citation statements)

References 41 publications

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“…Recently, a similar approach was applied for the TPR family, where increasing the stability of the interface between its repeats changed the folding from a multistate mechanism to a two-state one (32). In particular, a simple folding theory based on the capillarity model for propagating the linear protein (57)(58)(59) is in very good agreement with the simulation results. This simple model predicts that the folding rate of a protein with n repeating units is controlled by the energetics of the interface, and that its stability is determined by the ratio between the inter-and intrarepeat stabilities.…”

Section: Discussionmentioning

confidence: 68%

Modulation of Folding Kinetics of Repeat Proteins: Interplay between Intra- and Interdomain Interactions

Hagai

Azia

Trizac

et al. 2012

Biophysical Journal

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Repeat proteins have unique elongated structures that, unlike globular proteins, are quite modular. Despite their simple one-dimensional structure, repeat proteins exhibit intricate folding behavior with a complexity similar to that of globular proteins. Therefore, repeat proteins allow one to quantify fundamental aspects of the biophysics of protein folding. One important feature of repeat proteins is the interfaces between the repeating units. In particular, the distribution of stabilities within and between the repeats was previously suggested to affect their folding characteristics. In this study, we explore how the interface affects folding kinetics and cooperativity by investigating two families of repeat proteins, namely, the Ankyrin and tetratricopeptide repeat proteins, which differ in the number of interfacial contacts that are formed between their units as well as in their folding behavior. By using simple topology-based models, we show that modulating the energetic strength of the interface relative to that of the repeat itself can drastically change the protein stability, folding rate, and cooperativity. By further dissecting the interfacial contacts into several subsets, we isolated the effects of each of these groups on folding kinetics. Our study highlights the importance of interface connectivity in determining the folding behavior.

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Section: Discussionmentioning

confidence: 68%

Modulation of Folding Kinetics of Repeat Proteins: Interplay between Intra- and Interdomain Interactions

Hagai

Azia

Trizac

et al. 2012

Biophysical Journal

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“…As stated earlier, the naturally occurring heterodimeric monellin can be thought of as two disordered proteins that fold upon binding. In our simulations, the β2-β3 interactions form before the transition state, and thus most of the interchain interface is the folding nucleus . Furthermore, deleting these β2-β3 interactions suppresses structure formation in both “chains” of scMn.…”

Section: Discussionmentioning

confidence: 72%

“…In our simulations, the β2-β3 interactions form before the transition state, and thus most of the interchain interface is the folding nucleus. 55 Furthermore, deleting these β2-β3 interactions suppresses structure formation in both "chains" of scMn. We conclude that having a folding nucleus that spans the two chains keeps them disordered until they encounter each other.…”

Section: ■ Discussionmentioning

confidence: 99%

Intrinsic Disorder in a Well-Folded Globular Protein

2018

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The folded structure of the heterodimeric sweet protein monellin mimics single-chain proteins with topology β1-α1-β2-β3-β4-β5 (chain A: β3-β4-β5; chain B: β1-α1-β2). Furthermore, like naturally occurring single-chain proteins of a similar size, monellin folds cooperatively with no detectable intermediates. However, the two monellin chains, A and B, are marginally structured in isolation and fold only upon binding to each other. Thus, monellin presents a unique opportunity to understand the design of intrinsically disordered proteins that fold upon binding. Here, we study the folding of a single-chain variant of monellin (scMn) using simulations of an all heavy-atom structure-based model. These simulations can explain mechanistic details derived from scMn experiments performed using several different structural probes. scMn folds cooperatively in our structure-based simulations, as is also seen in experiments. We find that structure formation near the transition-state ensemble of scMn is not uniformly distributed but is localized to a hairpin-like structure which contains one strand from each chain (β2, β3). Thus, the sequence and the underlying energetics of heterodimeric monellin promote the early formation of the interchain interface (β2-β3). By studying computational scMn mutants whose "interchain" interactions are deleted, we infer that this energy distribution allows the two protein chains to remain largely disordered when this interface is not folded. From these results, we suggest that cutting the protein backbone of a globular protein between residues which lie within its folding nucleus may be one way to construct two disordered fragments which fold upon binding.

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“…The theoretical framework of this model was first introduced by Portman et al (13)(14)(15) for the study of the protein folding problem, which demonstrated its usefulness in constructing the free energy surface of globular proteins (13)(14)(15)(16)(17). Later, Qi and Portman (18) implemented the model in the calculation of protein folding rates and the classification of folding patterns of two-state proteins (19). The essence of the variational model is to determine the folding pathway from unfolded to folded states by varying the constraints on each residue from small to large number, continuously.…”

Section: Introductionmentioning

confidence: 99%

A Variational Model for Oligomer-Formation Process of GNNQQNY Peptide from Yeast Prion Protein Sup35

Hong

Zhang

2012

Biophysical Journal

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Many human neurodegenerative diseases are associated with the aggregation of insoluble amyloid-like fibrous proteins. However, the processes by which the randomly diffused monomer peptides aggregate into the highly regulated amyloid fibril structures are largely unknown. We proposed a residue-level coarse-grained variational model for the investigation of the aggregation pathway for a small assembly of amyloid proteins, the peptide GNNQQNY from yeast prion protein Sup35. By examining the free energy surface, we identified the residue-level sequential pathways for double parallel and antiparallel β-peptides, which show that the central dry polar zipper structure is the major folding core in both cases. The critical nucleus size is determined to be three peptides for the homogeneous nucleation process, whereas the zig-zag growth pattern appears most favorably for heterogeneous nucleation. Consistent with the dock-and-lock mechanism, the aggregation process of free peptides to the fibril core was found to be highly cooperative. The quantitative validation with the computational simulations and experimental data demonstrated the usefulness of the proposed model in understanding the general mechanism of the amyloid fibril system.

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Capillarity-like growth of protein folding nuclei

Cited by 10 publications

References 41 publications

Modulation of Folding Kinetics of Repeat Proteins: Interplay between Intra- and Interdomain Interactions

Modulation of Folding Kinetics of Repeat Proteins: Interplay between Intra- and Interdomain Interactions

Intrinsic Disorder in a Well-Folded Globular Protein

A Variational Model for Oligomer-Formation Process of GNNQQNY Peptide from Yeast Prion Protein Sup35

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