Evaluation of the Stability of Folding Nucleus upon Mutation

Lonquety, Mathieu; Lacroix, Zoé; Chomilier, Jacques

doi:10.1007/978-3-540-88436-1_5

Cited by 4 publications

(4 citation statements)

References 32 publications

(39 reference statements)

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“…This is an enhancement of a first version that comprised only 116 PDB codes (Lonquety et al, 2008a). The distribution in the Topology level of CATH (Orengo et al, 1998), corresponding to the fold level of SCOP (Murzin et al, 1995), is given in Table 1, with the exception of 18 PDB codes unavailable in CATH.…”

Section: Datasetmentioning

confidence: 99%

Prediction of Stability upon Point Mutation in the Context of the Folding Nucleus

Lonquety

Chomilier²,

Παπανδρεου³

et al. 2010

OMICS: A Journal of Integrative Biology

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Proteins come in all shapes and sizes. Although it is possible to predict with reasonable success their structure from their sequence, the process of folding a chain of amino acids into its tertiary structure remains partially understood. This article addresses several characteristics pertaining to protein folding. The development of the Most Interacting Residues (MIR) algorithm, which dynamically simulates the early folding events, permits a reasonable ab initio prediction of the deeply buried critical residues involved in the formation of the protein core. The analysis of MIR positions with respect to protein 3D topology, in particular, to fragments called Tightened End Fragments (TEF) that might be good candidate for autonomous folding units, suggests that they are also essential for defining core stability. To validate this hypothesis, this study measures the sensitivity of MIR residues to point mutations. It is performed on a set of 385 proteins from a database that contains stability data calculated with five different algorithms. Tools have been developed to help the analysis and a consensus of the five methods is proposed. It results that positions predicted both as a MIR and a minimum of stability for the consensus are good candidates for the folding nucleus, and consequently their mutations may be hazardous.

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Section: Datasetmentioning

confidence: 99%

Prediction of Stability upon Point Mutation in the Context of the Folding Nucleus

Lonquety

Chomilier²,

Παπανδρεου³

et al. 2010

OMICS: A Journal of Integrative Biology

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“…The ability of Dmutant, two versions of I-Mutant 2.0, MUpro, and PoPMuSiC to detect folding nuclei affected by variations has been evaluated [ 34 ]. The dataset contained 1409 variations from the ProTherm and some methods were tested with the same data which they had been trained.…”

Section: Examples Of Performance Comparisonsmentioning

confidence: 99%

How to evaluate performance of prediction methods? Measures and their interpretation in variation effect analysis

2012

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BackgroundPrediction methods are increasingly used in biosciences to forecast diverse features and characteristics. Binary two-state classifiers are the most common applications. They are usually based on machine learning approaches. For the end user it is often problematic to evaluate the true performance and applicability of computational tools as some knowledge about computer science and statistics would be needed.ResultsInstructions are given on how to interpret and compare method evaluation results. For systematic method performance analysis is needed established benchmark datasets which contain cases with known outcome, and suitable evaluation measures. The criteria for benchmark datasets are discussed along with their implementation in VariBench, benchmark database for variations. There is no single measure that alone could describe all the aspects of method performance. Predictions of genetic variation effects on DNA, RNA and protein level are important as information about variants can be produced much faster than their disease relevance can be experimentally verified. Therefore numerous prediction tools have been developed, however, systematic analyses of their performance and comparison have just started to emerge.ConclusionsThe end users of prediction tools should be able to understand how evaluation is done and how to interpret the results. Six main performance evaluation measures are introduced. These include sensitivity, specificity, positive predictive value, negative predictive value, accuracy and Matthews correlation coefficient. Together with receiver operating characteristics (ROC) analysis they provide a good picture about the performance of methods and allow their objective and quantitative comparison. A checklist of items to look at is provided. Comparisons of methods for missense variant tolerance, protein stability changes due to amino acid substitutions, and effects of variations on mRNA splicing are presented.

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“…Segments that form loops in the folded state were identified [47]. The importance of the MIR elements was further validated by the simulation of mutations in these sequences and by the correlation with the known stabilities of 385 proteins with published stability data [48]. These studies of the MIR elements, which are located at the ends of long loops, strongly support the loop hypothesis.…”

Section: Introductionmentioning

confidence: 90%

Fast closure of long loops at the initiation of the folding transition of globular proteins studied by time-resolved FRET-based methods

Orevi

Rahamim

Shemesh

et al. 2014

Bio-Algorithms and Med-Systems

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The protein folding problem would be considered "solved" when it will be possible to "read genes", i.e., to predict the native fold of proteins, their dynamics, and the mechanism of fast folding based solely on sequence data. The long-term goal should be the creation of an algorithm that would simulate the stepwise mechanism of folding, which constrains the conformational space and in which random search for stable interactions is possible. Here, we focus attention on the initial phases of the folding transition starting with the compact disordered collapsed ensemble, in search of the initial sub-domain structural biases that direct the otherwise stochastic dynamics of the backbone. Our studies are designed to test the "loop hypothesis", which suggests that fast closure of long loop structures by non-local interactions between clusters of mainly non-polar residues is an essential conformational step at the initiation of the folding transition of globular proteins. We developed and applied experimental methods based on time-resolved resonance excitation energy transfer (trFRET) measurements combined with fast mixing methods and studied the initial phases of the folding of Escherichia coli adenylate kinase (AK). A series of AK mutants were prepared, in which the ends of selected backbone segments that form long closed loops or secondary structure elements were labeled by donors and acceptors of excitation energy. The end-to-end distance distributions of such segments were determined under equilibrium and during the fast folding transitions. These experiments show that three out of seven long loops that were labeled in the AK molecule are closed very early in the transition. The N terminal 26-residue loop (loop I) is closed in < 200 μs after the initiation of folding, while the β strand included in loop I is still disordered. The closure of the second 44-residue loop (loop II, which starts at the end of loop I) is also complete within < 300 μs. Four other loops as well as five secondary structures of the CORE domain of AK (an α helix and four β strands) are formed at a late step, at a rate of 0.5 ± 0.3 s -1 , the rate of the cooperative folding of the molecule. These experiments reveal a hierarchically ordered pathway of folding of the AK molecule, ranging from microseconds to seconds. The results reviewed here, obtained mainly from studying a small number of model proteins, support the counterintuitive mechanism whereby non-local interactions are effective in the initiation of the folding pathways. The experiments presented demonstrate the importance of mapping the rates of sub-domain structural transitions along the folding transition, in situ, in the context of the other sections of the chain, whether folded or disordered. These experiments also show the power of the time-resolved FRET measurements in achieving this goal. A large body of data obtained by theoretical and experimental studies that support, or can accommodate, the loop hypothesis is reviewed. We suggest that mapping multiple sub-domain structural tr...

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Evaluation of the Stability of Folding Nucleus upon Mutation

Cited by 4 publications

References 32 publications

Prediction of Stability upon Point Mutation in the Context of the Folding Nucleus

Prediction of Stability upon Point Mutation in the Context of the Folding Nucleus

How to evaluate performance of prediction methods? Measures and their interpretation in variation effect analysis

Fast closure of long loops at the initiation of the folding transition of globular proteins studied by time-resolved FRET-based methods

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