Obligatory steps in protein folding and the conformational diversity of the transition state

Martínez, José C.; Pisabarro, M. Teresa; Serrano, Luís

doi:10.1038/1418

Cited by 252 publications

(261 citation statements)

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“…A description of each of these intermediates was obtained by collecting characteristic structures from the simulation data. Most importantly, the structures that are produced share many features with those generated on the basis of experiment (21)(22)(23)(24)(25)(26). The present study demonstrates the utility of supplementing experiment with simulation and illustrates the important role that simplified protein models can play in increasing our understanding of protein folding.…”

mentioning

confidence: 70%

“…Residues in the distal ␤-hairpin are also highly structured in the transition state for the ␣-spectrin SH3 domain (24). Another study concluded that formation of the distal loop in ␣-spectrin SH3 in an obligatory step in forming the transition state, because it is necessary to bring together strands ␤3 and ␤4 (25). With the exception of certain transition-state features that are not conserved among these homologous proteins [i.e., structuring of the C-terminal residues in the RT loop in src SH3 (23) and of the 3 10 helix in ␣-spectrin SH3 (24)], a strong correlation is observed between experiment and our simulation results.…”

Section: )mentioning

confidence: 99%

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Sparsely populated folding intermediates of the Fyn SH3 domain: Matching native-centric essential dynamics and experiment

Ollerenshaw

Kaya

Chan

et al. 2004

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

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confidence: 70%

Section: )mentioning

confidence: 99%

Sparsely populated folding intermediates of the Fyn SH3 domain: Matching native-centric essential dynamics and experiment

Ollerenshaw

Kaya

Chan

et al. 2004

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

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“…4 a and b emphasize the successive structures before entering͞escaping the ␣-helical basin. These two trajectories show that there are several, perhaps many, pathways for these reactions, and that this system has a transition region with more than one transition state, rather than a single transition state, as classical chemical kinetics would suggest (35,40). The two trajectories are presented here as an indication of the effect of entropy on the folding and unfolding processes.…”

Section: Methodsmentioning

confidence: 99%

“…Similarly, the transition time of the unfolding reaction, ␣3␤, was defined as the time required to unwind the helix and to obtain a structure with 0% ␣-helical content and 83% ␤-sheet. The ␣-helical and ␤-sheet contents of any conformation of the conformation samples and of the folding͞unfolding trajectories were calculated by using the DSSP program (35). In addition, to estimate the effect of solvation on the stability of the two states of Ala 12 in vacuum, we collected 200 ␣-helical conformations and 200 ␤-hairpin conformations of Ala 12 , each sampled along 0.4-ns trajectories at 300 K by using vacuum, the EEF1 implicit solvation model, and the TIP3P explicit water models (36).…”

Section: Methodsmentioning

confidence: 99%

Solvent effects on the energy landscapes and folding kinetics of polyalanine

Levy

Jortner

Becker

2001

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

146

132

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The effect of a solvation on the thermodynamics and kinetics of polyalanine (Ala12) is explored on the basis of its energy landscapes in vacuum and in an aqueous solution. Both energy landscapes are characterized by two basins, one associated with ␣-helical structures and the other with coil and ␤-structures of the peptide. In both environments, the basin that corresponds to the ␣-helical structure is considerably narrower than the basin corresponding to the ␤-state, reflecting their different contributions to the entropy of the peptide. In vacuum, the ␣-helical state of Ala12 constitutes the native state, in agreement with common helical propensity scales, whereas in the aqueous medium, the ␣-helical state is destabilized, and the ␤-state becomes the native state. Thus solvation has a dramatic effect on the energy landscape of this peptide, resulting in an inverted stability of the two states. Different folding and unfolding time scales for Ala12 in hydrophilic and hydrophobic chemical environments are caused by the higher entropy of the native state in water relative to vacuum. The concept of a helical propensity has to be extended to incorporate environmental solvent effects.T he chemical environment exerts a fundamental influence on the structure, thermodynamics, and dynamics of polypeptides. Particularly, the solvent may affect the dynamics and structure of the polypeptide and consequently alter its function, as has been demonstrated in a variety of biologically important phenomena, ranging from the rate of oxygen uptake in myoglobin to the stabilization of opposite-charged side-chain pairs at the surface of proteins (1, 2). The variance of the properties of a polypeptide in different solvents depends on the nature of the solvent-polypeptide intermolecular interactions, which lead to a rich repertoire of phenomena. These interactions involve the effect of organic solvents on the destabilization of the hydrophobic core and the exposure of side chains, as well as the opposite effects of aqueous solvents on the protein structures favoring the hydrophilic protein surface and the hydrophobic core (1, 3). Theoretical and computational evidence (4-6) for medium effects on polypeptide structures has accumulated. Following the Zimm-Bragg theory of the helix-coil equilibrium (7), it has been established that short polypeptides should not form helices in water. Indeed, numerous studies report that the relative tendency for helix formation in water is low at physiological temperatures (6,8).The structure of polyalanine peptides is of considerable interest as, in general, regardless of specific chemical environments, the commonly reported secondary structure propensity scales for amino acids (9-11) rank alanine as having the highest ␣-helical propensity. However, experimental (12-14) and computational (4-6, 15-23) studies showed that polyalanines tend to adopt random-coil conformations in aqueous solution. The ambiguity of the helical propensities, even for alanine, which is known as an excellent helix former, may indic...

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“…However, in protein folding studies, interpretational issues arise because most values are fractional, generally lying in the range of 0.1-0.5 (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). These intermediate values might be due to partial structure formation in the TS or the presence of multiple TS structures.…”

mentioning

confidence: 99%

Differences in the folding transition state of ubiquitin indicated by φ and ψ analyses

Sosnick

Dothager

Krantz

2004

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

101

155

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We compare the folding transition state (TS) of ubiquitin previously identified by using analysis to that determined by using analysis. Both methods attempt to identify interactions and their relative populations at the rate-limiting step for folding. The TS ensemble derived from analysis has an extensive native-like chain topology, with a four-stranded ␤-sheet network and a portion of the major helix. According to analysis, however, the TS is much smaller and more polarized, with only a local helix͞ hairpin motif. We find that structured regions can have values far from unity, the canonical value for such sites, because of structural relaxation of the TS. Consequently, these sites may be incorrectly interpreted as contributing little to the structure of the TS. These results stress the need for caution when interpreting and drawing conclusions from analysis alone and highlight the need for more specific tools for examining the structure and energetics of the TS ensemble.multiple pathways ͉ phi analysis ͉ protein folding ͉ transition state M utational analysis has been a major method for characterizing the structure of transition states (TSs) for protein folding (1, 2) and other reactions (3,4). In this approach, the energetic effect of an amino acid substitution on the foldingactivation energy relative to its effect on equilibrium stability, quantified as , is interpreted as the extent to which a mutated residue is involved in the formation of the TS. Values of zero and one are taken to indicate that the influence of the side chain is either absent or fully present, respectively, in the TS.However, in protein folding studies, interpretational issues arise because most values are fractional, generally lying in the range of 0.1-0.5 (5-14). These intermediate values might be due to partial structure formation in the TS or the presence of multiple TS structures. Furthermore, if multiple, alternative TSs exist, a destabilizing mutation will reduce the fraction of states in the ensemble that involve this residue and, thus, generate a lower than expected value (8,14,15). For example, our earlier work with the GCN4 coiled coil protein found low single-site values (16), which turned out to be caused by alternative nucleation positions rather than by the lack of participation by the mutated position (8,11).Even in the case of a single pathway, a mutation can shift the location of the TS either through Hammond or anti-Hammond behavior (15). In general, the effects of an amino acid substitution can depend on an indeterminate combination of local, long-range, native, and even nonnative interactions, and secondary structure preferences. As a consequence, the translation of fractional energetic changes into the language of TS structure is difficult. Some of the problems may be addressable with multiple mutations at a given site (12,15).The analysis methodology overcomes several of these shortcomings by identifying structure and shifts in TS populations upon perturbation (11). In this method, engineered bi-His metal ion bindin...

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Obligatory steps in protein folding and the conformational diversity of the transition state

Cited by 252 publications

References 54 publications

Sparsely populated folding intermediates of the Fyn SH3 domain: Matching native-centric essential dynamics and experiment

Sparsely populated folding intermediates of the Fyn SH3 domain: Matching native-centric essential dynamics and experiment

Solvent effects on the energy landscapes and folding kinetics of polyalanine

Differences in the folding transition state of ubiquitin indicated by φ and ψ analyses

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