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

Lonquety, Mathieu; Chomilier, Jacques; Παπανδρεου, Νικολαοσ; Lacroix, Zoé

doi:10.1089/omi.2009.0022

Cited by 6 publications

(8 citation statements)

References 26 publications

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“…The results of the simulation revealed a significant trend of burial of the MIR elements at the initiation of the folding process. The importance of the MIR elements was further validated by the simulation of mutations in these sequences and correlation with the known stabilities of 385 proteins with published stability data (Lonquety et al 2009). These studies of the MIR elements, which are located are at the ends of long loops, strongly support the loop hypothesis.…”

Section: O'neill Et Al (O'neill and Robert Matthews 2000)mentioning

confidence: 92%

“…Papandreou and Chomilier and coworkers (Lonquety et al 2009;Papandreou et al 2004;Prudhomme and Chomilier 2009) used native fold analysis and simulations to further develop the concept of closed loops as early folding structures and to elucidate the mechanism of folding. An algorithm was developed for the recognition of the residues involved in the loop closure interaction, which were named Most Interacting Residues (MIR); this was followed by dynamic simulation of the early folding events.…”

Section: O'neill Et Al (O'neill and Robert Matthews 2000)mentioning

confidence: 99%

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The loop hypothesis: contribution of early formed specific non-local interactions to the determination of protein folding pathways

et al. 2013

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The extremely fast and efficient folding transition (in seconds) of globular proteins led to the search for some unifying principles embedded in the physics of the folding polypeptides. Most of the proposed mechanisms highlight the role of local interactions that stabilize secondary structure elements or a folding nucleus as the starting point of the folding pathways, i.e., a "bottom-up" mechanism. Nonlocal interactions were assumed either to stabilize the nucleus or lead to the later steps of coalescence of the secondary structure elements. An alternative mechanism was proposed, an "up-down" mechanism in which it was assumed that folding starts with the formation of very few non-local interactions which form closed long loops at the initiation of folding. The possible biological advantage of this mechanism, the "loop hypothesis", is that the hydrophobic collapse is associated with ordered compactization which reduces the chance for degradation and misfolding. In the present review the experiments, simulations and theoretical consideration that either directly or indirectly support this mechanism are summarized. It is argued that experiments monitoring the time-dependent development of the formation of specifically targeted early-formed sub-domain structural elements, either long loops or secondary structure elements, are necessary. This can be achieved by the timeresolved FRET-based "double kinetics" method in combination with mutational studies. Yet, attempts to improve the time resolution of the folding initiation should be extended down to the sub-microsecond time regime in order to design experiments that would resolve the classes of proteins which first fold by local or non-local interactions.

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Section: O'neill Et Al (O'neill and Robert Matthews 2000)mentioning

confidence: 92%

Section: O'neill Et Al (O'neill and Robert Matthews 2000)mentioning

confidence: 99%

The loop hypothesis: contribution of early formed specific non-local interactions to the determination of protein folding pathways

et al. 2013

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“…It then gives a precise idea of positions where a mutation that would change the hydrophobicity of the side chain is likely to have important consequences on the structure. MIR and its extension SMIR are also integrated in the whole SPROUTS analysis system, where the results can be compared to stability analyses [10,38,39]. MIR is listed as a service of the Mobyle portal for bioinformatics analyses (http://mobyle.rpbs.univparis-diderot.fr/), developed joint ly by the Institut Pasteur Biology IT Center and RPBS that supports linear workflows integrating various services and databanks [40].…”

Section: Discussionmentioning

confidence: 99%

“…We will explore how MIR can be used as an index to guide the alignment of proteins, therefore identifying areas of similarities that typically are not captured by traditional alignment methods [44]. A second promising area resides in integrating MIR with stability analyses to better predict the impact of mutations on protein structure [10,38,39]. We will investigate how the consensus method consisting of the average of various stability analyses currently made available in SPROUTS [12] can be improved for the prediction of the dramatic impact of mutation of protein structures with MIR.…”

Section: Discussionmentioning

confidence: 99%

Protein intrachain contact prediction with most interacting residues (MIR)

Acuna

Lacroix

Παπανδρεου

et al. 2014

Bio-Algorithms and Med-Systems

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The transition state ensemble during the folding process of globular proteins occurs when a sufficient number of intrachain contacts are formed, mainly, but not exclusively, due to hydrophobic interactions. These contacts are related to the folding nucleus, and they contribute to the stability of the native structure, although they may disappear after the energetic barrier of transition states has been passed. A number of structure and sequence analyses, as well as protein engineering studies, have shown that the signature of the folding nucleus is surprisingly present in the native three-dimensional structure, in the form of closed loops, and also in the early folding events. These findings support the idea that the residues of the folding nucleus become buried in the very first folding events, therefore helping the formation of closed loops that act as anchor structures, speed up the process, and overcome the Levinthal paradox. We present here a review of an algorithm intended to simulate in a discrete space the early steps of the folding process. It is based on a Monte Carlo simulation where perturbations, or moves, are randomly applied to residues within a sequence. In contrast with many technically similar approaches, this model does not intend to fold the protein but to calculate the number of non-covalent neighbors of each residue, during the early steps of the folding process. Amino acids along the sequence are categorized as most interacting residues (MIRs) or least interacting residues. The MIR method can be applied under a variety of circumstances. In the cases tested thus far, MIR has successfully identified the exact residue whose mutation causes a switch in conformation. This follows with the idea that MIR identifies residues that are important in the folding process. Most MIR positions correspond to hydrophobic residues; correspondingly, MIRs have zero or very low accessible surface area. Alongside the review of the MIR method, we present a new postprocessing method called smoothed MIR (SMIR), which refines the original MIR method by exploiting the knowledge of residue hydrophobicity. We review known results and present new ones, focusing on the ability of MIR to predict structural changes, secondary structure, and the improved precision with the SMIR method.

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“…Chomilier et al [44][45][46] used native fold analysis and simulations to develop the concept of closed loops as early folding structures and to elucidate the mechanism of folding [44]. An algorithm was developed for the identification of the residues involved in the loop closure interaction, which were named most interacting residues (MIR).…”

Section: Introductionmentioning

confidence: 99%

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

Cited by 6 publications

References 26 publications

The loop hypothesis: contribution of early formed specific non-local interactions to the determination of protein folding pathways

The loop hypothesis: contribution of early formed specific non-local interactions to the determination of protein folding pathways

Protein intrachain contact prediction with most interacting residues (MIR)

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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