Predicting repeat protein folding kinetics from an experimentally determined folding energy landscape

Street, Timothy O.; Barrick, Doug

doi:10.1002/pro.9

Cited by 16 publications

(10 citation statements)

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“…4 ) as the separation between repeats increases. The predicted global correlation length of ∼1.4 repeated units is remarkably close to that inferred from statistical mechanical analysis of folding experiments [ 35 , 36 ] and folding simulations [ 37 ]. These predictions are based on approximating long-range covariations from sets of pair-wise inter-repeat interactions, allowing for the application of the procedure for arbitrarily large structures for which an exact calculation would be computationally prohibitive.…”

Section: Discussionsupporting

confidence: 76%

Capturing coevolutionary signals inrepeat proteins

et al. 2015

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BackgroundThe analysis of correlations of amino acid occurrences in globular domains has led to the development of statistical tools that can identify native contacts – portions of the chains that come to close distance in folded structural ensembles. Here we introduce a direct coupling analysis for repeat proteins – natural systems for which the identification of folding domains remains challenging.ResultsWe show that the inherent translational symmetry of repeat protein sequences introduces a strong bias in the pair correlations at precisely the length scale of the repeat-unit. Equalizing for this bias in an objective way reveals true co-evolutionary signals from which local native contacts can be identified. Importantly, parameter values obtained for all other interactions are not significantly affected by the equalization. We quantify the robustness of the procedure and assign confidence levels to the interactions, identifying the minimum number of sequences needed to extract evolutionary information in several repeat protein families.ConclusionsThe overall procedure can be used to reconstruct the interactions at distances larger than repeat-pairs, identifying the characteristics of the strongest couplings in each family, and can be applied to any system that appears translationally symmetric.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-015-0648-3) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 76%

Capturing coevolutionary signals inrepeat proteins

et al. 2015

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“…Energy landscape theory arguments [36] predict that non-native traps 304 would raise bigger free energy barriers in the folding of large proteins, so selection 305 against misfolding should be stronger for longer proteins than shorter ones. To avoid misfolded traps, repeat protein may have to be more homogeneous and favorable as they 307 get longer, nucleating folding and propagating to near 308 neighbours [6], [10], [11], [12], [13], which is in line with our findings in the natural 309 proteins. We propose that long, heterogeneous and less favorable repeat arrays may not 310 fold robustly in vivo and may be detrimental to fitness, so we will not find them in 311 nature.…”

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confidence: 77%

Large Ankyrin repeat proteins are formed with similar and energetically favorable units

Galpern

Freiberger

Ferreiro

2019

Preprint

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Ankyrin containing proteins are one of the most abundant repeat protein families present in all extant organisms. They are made with tandem copies of similar amino acid stretches that fold into elongated architectures. Here, we build and curated a dataset of 200 thousand proteins that contain 1,2 million Ankyrin regions and characterize the abundance, structure and energetics of the repetitive regions in natural proteins. We found that there is a continuous roughly exponential variety of array lengths with an exceptional frequency at 24 repeats. We describe that individual repeats are seldom interrupted with long insertions and accept few deletions, consistently with the know tertiary structures. We found that longer arrays are made up of repeats that are more similar to each other than shorter arrays, and display more favourable folding energy, hinting at their evolutionary origin. The array distributions show that there is a physical upper limit to the size of an array of Ankyrin repeats of about 120 copies, consistent with the limit found in nature. Analysis of the identity patterns within the arrays suggest that they may have originated by sequential copies of more than one Ankyrin unit. Author summaryRepeat proteins are coded in tandem copies of similar amino acid stretches. We built and curated a large dataset of Ankyrin containing proteins, one of the most abundant families of repeat proteins, and characterized the structure of the arrays formed by the repetitions. We found that large arrays are constructed with repetitions that are more similar to each other than shorter arrays. Also, the largest the array, the more energetically favourable its folding energy is. We speculate about the mechanistic origin of large arrays and hint into their evolutionary dynamics.Natural proteins that are formed with repetitions of stretches of amino-acids are 2 abundant in extant organisms [1]. Some proteins contain repetitions of short stretches, 3 forming fibrillate structures like collagen, and some contain longer repetitions of 4 globular domains like beads on a string. In between, there is a class of proteins that is 5 formed with tandem repetitions of similar stretches of about 30∼40 residues. These kind 6 of proteins (from now on repeat proteins) are present in all organisms and are believed 7 to be ancient systems [2]. Typically these polypeptides form elongated structures where 8 November 25, 2019 1/23 each repeat motifs packs against its nearest neighbors, stabilizing an overall 9super-helical fold [3]. Since most of the structural characterization of these proteins 10 were performed on model systems of short arrays that are experimentally amenable, we 11 aim at characterizing the overall structures of an abundant family of proteins. 12Ankyrin repeat proteins (ANKs) are usually described as formed with linear arrays 13 of tandem copies of a 33 residues length motif that fold to a α-loop-α − β-hairpin/loop. 14 Being one of the most common repeat proteins in nature, these molecules are believed 15 to function as sp...

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“…The structures of partially unfolded forms at equilibrium with native protein provide information on protein folding intermediates . The current understanding of protein folding holds that proteins fold along the surface of funnel‐like conformational energy landscapes, which contain an ensemble of partially unfolded forms in local energy minima . This view of protein folding suggests that, once folded, a natively folded protein makes transient excursions to the partially unfolded forms.…”

Section: Introductionmentioning

confidence: 99%

Structure of a partially unfolded form of Escherichia coli dihydrofolate reductase provides insight into its folding pathway

2014

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Proteins frequently fold via folding intermediates that correspond to local minima on the conformational energy landscape. Probing the structure of the partially unfolded forms in equilibrium under native conditions can provide insight into the properties of folding intermediates. To elucidate the structures of folding intermediates of Escherichia coli dihydrofolate reductase (DHFR), we investigated transient partial unfolding of DHFR under native conditions. We probed the structure of a high-energy conformation susceptible to proteolysis (cleavable form) using native-state proteolysis. The free energy for unfolding to the cleavable form is clearly less than that for global unfolding. The dependence of the free energy on urea concentration (m-value) also confirmed that the cleavable form is a partially unfolded form. By assessing the effect of mutations on the stability of the partially unfolded form, we found that native contacts in a hydrophobic cluster formed by the F-G and Met-20 loops on one face of the central b-sheet are mostly lost in the partially unfolded form. Also, the folded region of the partially unfolded form is likely to have some degree of structural heterogeneity. The structure of the partially unfolded form is fully consistent with spectroscopic properties of the nearnative kinetic intermediate observed in previous folding studies of DHFR. The findings suggest that the last step of the folding of DHFR involves organization in the structure of two large loops, the F-G and Met-20 loops, which is coupled with compaction of the rest of the protein.

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Predicting repeat protein folding kinetics from an experimentally determined folding energy landscape

Cited by 16 publications

References 49 publications

Capturing coevolutionary signals inrepeat proteins

Capturing coevolutionary signals inrepeat proteins

Large Ankyrin repeat proteins are formed with similar and energetically favorable units

Structure of a partially unfolded form of Escherichia coli dihydrofolate reductase provides insight into its folding pathway

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