Context-dependent contributions of backbone hydrogen bonding to β-sheet folding energetics

Deechongkit, Songpon; Nguyen, Houbi; Powers, Evan T.; Dawson, Philip E.; Gruebele, Martin

doi:10.1038/nature02611

Cited by 268 publications

(331 citation statements)

References 29 publications

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“…In contrast, for intrastrand stacking, S, the stacking of base pairs is more favoured in water by 1·2 kcal mol −1 , while interstrand stacking, IS, is nearly identical in aqueous and apolar matrices (ΔΔE = −0·12 kcal mol −1 ). These results are in line with the increased strength of buried H-bonds (Deechongkit et al 2004) and also known from the experimental appearance of strong hydrogen-bonded dimers in polyethylene compared with water solution (Norden, 1977).…”

Section: Resultssupporting

confidence: 87%

A stretched conformation of DNA with a biological role?

Bosaeus

Reymer

Beke‐Somfai

et al. 2017

Quart. Rev. Biophys.

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Abstract. We have discovered a well-defined extended conformation of double-stranded DNA, which we call Σ-DNA, using laser-tweezers force-spectroscopy experiments. At a transition force corresponding to free energy change ΔG = 1·57 ± 0·12 kcal (mol base pair) −1 60 or 122 base-pair long synthetic GC-rich sequences, when pulled by the 3′−3′ strands, undergo a sharp transition to the 1·52 ± 0·04 times longer Σ-DNA. Intriguingly, the same degree of extension is also found in DNA complexes with recombinase proteins, such as bacterial RecA and eukaryotic Rad51. Despite vital importance to all biological organisms for survival, genome maintenance and evolution, the recombination reaction is not yet understood at atomic level. We here propose that the structural distortion represented by Σ-DNA, which is thus physically inherent to the nucleic acid, is related to how recombination proteins mediate recognition of sequence homology and execute strand exchange. Our hypothesis is that a homogeneously stretched DNA undergoes a 'disproportionation' into an inhomogeneous Σ-form consisting of triplets of locally B-like perpendicularly stacked bases. This structure may ensure improved fidelity of base-pair recognition and promote rejection in case of mismatch during homologous recombination reaction. Because a triplet is the length of a gene codon, we speculate that the structural physics of nucleic acids may have biased the evolution of recombinase proteins to exploit triplet base stacks and also the genetic code.

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Section: Resultssupporting

confidence: 87%

A stretched conformation of DNA with a biological role?

Bosaeus

Reymer

Beke‐Somfai

et al. 2017

Quart. Rev. Biophys.

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“…Each such coordinate can be probed by ⌽, which ϭ ⌬⌬G ‡-D ͞⌬⌬G N-D for a prescribed mutation of a side chain or even backbone moiety (40,41). ⌽ effectively probes a local reaction coordinate based on Q i .…”

Section: ⌽ As An Index Of Local Reaction Coordinatesmentioning

confidence: 99%

Relationship of Leffler (Brønsted) α values and protein folding Φ values to position of transition-state structures on reaction coordinates

Fersht

2004

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

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The positions of transition states along reaction coordinates ( r ‡ ) for simple chemical reactions are often estimated from Leffler α values, the slope of plots of Δ G ‡ (activation energy) versus Δ G 0 (equilibrium free energy) for a series of structural variants. Protein folding is more complex than simple chemical reactions and has a multitude of reaction coordinates. Φ-Value analysis measures degree of structure formation at individual residues in folding transition states from the ratio ΔΔ G ‡ /ΔΔ G 0 for mutations. α values are now being used to analyze protein folding by lumping series of Φ values into single plots. But, there are discrepancies in the values of α for folding with more classical measures of the extent of structure formation, which I rationalize here. I show for chemical reactions with just a single reaction coordinate that α = r ‡ only for limiting cases, such as for reactants and products being in parabolic energy wells of identical curvature. Otherwise, α can differ radically from r ‡ , with α being determined just by the angles of intersection of reactant and product energy surfaces. Φ is an index of the progress of a local, energy-based reaction coordinate at the global transition state: Φ <0.5 corresponds to <50% progress of the local coordinate at the global transition state and Φ >0.5 means >50%. Protein Leffler plots can force different local indexes to a single fit and give skewed underestimates of the extent of global structure formation in transition states that differ from other measures of structure formation.

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“…This issue is further complicated by the possibility of nonnative interactions, which can generate nonzero values for what should otherwise be unstructured residues. Nevertheless, a recent study of the three-strand Pin WW domain probing hydrogen bond formation (site-resolved amide to ester changes) did observe qualitative agreement between mutational values (26).…”

Section: Discussionmentioning

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.

102

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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Context-dependent contributions of backbone hydrogen bonding to β-sheet folding energetics

Cited by 268 publications

References 29 publications

A stretched conformation of DNA with a biological role?

A stretched conformation of DNA with a biological role?

Relationship of Leffler (Brønsted) α values and protein folding Φ values to position of transition-state structures on reaction coordinates

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

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