n→π* interactions in proteins

Bartlett, Gail J.; Choudhary, Amit; Raines, Ronald T.; Woolfson, Derek N.

doi:10.1038/nchembio.406

Cited by 348 publications

(478 citation statements)

References 48 publications

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“…Another possible stabilizing factor is the n→π* interaction between adjacent peptide bonds (44). Simulations have suggested that dipole-dipole interactions between peptide bonds, which correspond to the quantum mechanical n→π* interactions, can explain the self-association of polyglycine peptides (25,45).…”

Section: Significancementioning

confidence: 99%

Perplexing cooperative folding and stability of a low-sequence complexity, polyproline 2 protein lacking a hydrophobic core

Gates

Baxa

et al. 2017

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

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The burial of hydrophobic side chains in a protein core generally is thought to be the major ingredient for stable, cooperative folding. Here, we show that, for the snow flea antifreeze protein (sfAFP), stability and cooperativity can occur without a hydrophobic core, and without α-helices or β-sheets. sfAFP has low sequence complexity with 46% glycine and an interior filled only with backbone H-bonds between six polyproline 2 (PP2) helices. However, the protein folds in a kinetically two-state manner and is moderately stable at room temperature. We believe that a major part of the stability arises from the unusual match between residue-level PP2 dihedral angle bias in the unfolded state and PP2 helical structure in the native state. Additional stabilizing factors that compensate for the dearth of hydrophobic burial include shorter and stronger H-bonds, and increased entropy in the folded state. These results extend our understanding of the origins of cooperativity and stability in protein folding, including the balance between solvent and polypeptide chain entropies.protein folding | cooperativity | kinetics | PP2 | hydrogen bonding T he basis of protein-folding stability and cooperativity remains a topic of great interest (1, 2). Most studies have focused on proteins with hydrophobic cores containing α-helices and β-sheets. Here, we study the folding of snow flea antifreeze protein (sfAFP), a globular protein that lacks these features. The 81-residue protein has a novel fold that is distinct from other proteins (3-6), containing only polyproline 2 (PP2) helices and turns with a core filled with H-bonds and no hydrophobic groups (Fig. 1).The H-bond network between the PP2 helices (6), PP2 1-6 , requires close packing, which would be precluded by the presence of a C β atom. Thus, the PP2 helices are defined by glycine (Gly) repeats (GXX or GGX, where X is any other amino acid), which enable the hydrogen-bond network. As a consequence, the sfAFP molecule has a low-complexity glycine-rich sequence [37/81 Gly residues, or 46%; typical is 6, or 7% (7)]. The sfAFP core is well packed with essentially no interior void volumes, even when probed using a 0.5-Å radius sphere (8). sfAFP also contains two disulfide bonds, C1-C28 and C13-C43.Notably, no side chains are buried in sfAFP's core (2). All 12 hydrophobic side chains (V 4 , K 2 , and P 6 ) are surface exposed. Upon folding, sfAFP buries about 20 Å 2 ·res −1 of hydrophobic surface area compared with an average of 50 Å 2 ·res −1 for a set of 34 proteins of similar size (Fig. 2A). The difference equates to a decrease in stability of ∼1 or 1.4 kcal·mol −1 ·res −1 , assuming a surface tension coefficient of γ ∼ 34 or 47 cal·mol −1 ·Å −2 based on classical (9) or Flory-Huggins theory (10), respectively. Even the lower bound of 1 kcal·mol −1 ·res −1 represents a significant stability loss, and it is not obvious which energetic terms could compensate for the reduction in hydrophobic burial.Because hydrophobic burial is generally regarded as the basis of protein stability a...

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Section: Significancementioning

confidence: 99%

Perplexing cooperative folding and stability of a low-sequence complexity, polyproline 2 protein lacking a hydrophobic core

Gates

Baxa

et al. 2017

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

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“…This interaction, which is reminiscent of the Bü rgi-Dunitz trajectory for nucleophilic addition to a carbonyl group, [17][18][19] induces a short contact between the nucleophile and the carbonyl carbon in which the van der Waals surfaces of the nucleophile and carbon interpenetrate. 10,12 This interaction has been identified in small molecules, such as c-aminobutyric acid 20 and aspirin, 21 and larger molecular systems, including peptides, 16 peptoids, 22,23 and proteins, 8 and could have directed the prebiotic genesis of ribonucleotides. 24 We suspected that the electron-deficient carbonyl carbon of the imidazolidinone ring could interact with a proximal nucleophilic donor.…”

Section: Introductionmentioning

confidence: 99%

“…8 Such an interaction, which we refer to as an ''n!p* interaction,'' 9-16 involves delocalization of the electron lone pair (n) of the nucleophilic donor into the antibonding orbital (p*) of the carbonyl group acceptor. This interaction, which is reminiscent of the Bü rgi-Dunitz trajectory for nucleophilic addition to a carbonyl group, [17][18][19] induces a short contact between the nucleophile and the carbonyl carbon in which the van der Waals surfaces of the nucleophile and carbon interpenetrate.…”

Section: Introductionmentioning

confidence: 99%

A conserved interaction with the chromophore of fluorescent proteins

2011

Self Cite

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The chromophore of fluorescent proteins, including the green fluorescent protein (GFP), contains a highly conjugated imidazolidinone ring. In many fluorescent proteins, the carbonyl group of the imidazolidinone ring engages in a hydrogen bond with the side chain of an arginine residue. Prior studies have indicated that such an electrophilic carbonyl group in a protein often accepts electron density from a main-chain oxygen. A survey of high-resolution structures of fluorescent proteins indicates that electron lone pairs of a main-chain oxygen-Thr62 in GFP-donate electron density into an antibonding orbital of the imidazolidinone carbonyl group. This nfip* electron delocalization prevents structural distortion during chromophore excitation that could otherwise lead to fluorescence quenching. In addition, this interaction is present in on-pathway intermediates leading to the chromophore, and thus could direct its biogenesis. Accordingly, this nfip* interaction merits inclusion in computational and photophysical analyses of the chromophore, and in speculations about the molecular evolution of fluorescent proteins.

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“…We found n!p* interactions in 31% of residue-steps, which agrees with the average of 34% found previously. 12 Ten percentage of the Ca-H groups made hydrogen bonds to C@O groups, which is in line with the proportion identified by Derewenda et al 5 Turning to CH X bonds (donated by side-chain CH 3 , CH 2 , or CH groups), we find that 10% of all such available groups in the dataset formed these weak hydrogen bonds, a much reduced proportion compared with the 36% found by Yesselman et al 9 However, this discrepancy can probably be explained in that our analysis only considers hydrogen bonds accepted by main-chain C@O groups and not other hydrogen bond acceptors.…”

Section: Prevalence Of "Weaker" Interactionsmentioning

confidence: 99%

“…2 In addition, weaker donor groups such as Ca-H and methyl-H are also possible contributors to protein stability. [5][6][7][8][9] More specifically, other hydrogen-bond-like, NCIs have been implicated, including the n!p* interaction [10][11][12] and methyl-p interactions. 13,14 These particular interactions are much weaker than canonical hydrogen bonds: the latter are typically worth 3-10 kcal/ mol 15,16 ; whereas, n!p* interactions are estimated at 0.7-1.2 kcal/mol, 10,16 and methyl-p interactions at 0.9-1.5 kcal/mol.…”

Section: Introductionmentioning

confidence: 99%

On the satisfaction of backbone‐carbonyl lone pairs of electrons in protein structures

Bartlett

Woolfson

2016

Protein Science

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Protein structures are stabilized by a variety of noncovalent interactions (NCIs), including the hydrophobic effect, hydrogen bonds, electrostatic forces and van der Waals' interactions. Our knowledge of the contributions of NCIs, and the interplay between them remains incomplete. This has implications for computational modeling of NCIs, and our ability to understand and predict protein structure, stability, and function. One consideration is the satisfaction of the full potential for NCIs made by backbone atoms. Most commonly, backbone-carbonyl oxygen atoms located within a-helices and b-sheets are depicted as making a single hydrogen bond. However, there are two lone pairs of electrons to be satisfied for each of these atoms. To explore this, we used operational geometric definitions to generate an inventory of NCIs for backbone-carbonyl oxygen atoms from a set of high-resolution protein structures and associated molecular-dynamics simulations in water. We included more-recently appreciated, but weaker NCIs in our analysis, such as nfip* interactions, Ca-H bonds and methyl-H bonds. The data demonstrate balanced, dynamic systems for all proteins, with most backbone-carbonyl oxygen atoms being satisfied by two NCIs most of the time. Combinations of NCIs made may correlate with secondary structure type, though in subtly different ways from traditional models of a-and b-structure. In addition, we find examples of under-and over-satisfied carbonyl-oxygen atoms, and we identify both sequencedependent and sequence-independent secondary-structural motifs in which these reside. Our analysis provides a more-detailed understanding of these contributors to protein structure and stability, which will be of use in protein modeling, engineering and design.

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n→π* interactions in proteins

Cited by 348 publications

References 48 publications

Perplexing cooperative folding and stability of a low-sequence complexity, polyproline 2 protein lacking a hydrophobic core

Perplexing cooperative folding and stability of a low-sequence complexity, polyproline 2 protein lacking a hydrophobic core

A conserved interaction with the chromophore of fluorescent proteins

On the satisfaction of backbone‐carbonyl lone pairs of electrons in protein structures

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