Hyperconjugation Contributes to the Bimodal Distribution of Glycine Conformations Observed in Protein Three‐Dimensional Structures

Abstract

Unravelling the mystery of protein folding has been a primary goal of the biological sciences since Anfinsen's seminal experiments demonstrated the connection between a protein's amino acid sequence and its active three-dimensional conformation.[1] Since then, there has been steady progress in the experimental, [2] theoretical, [3] analytical [4] and predictive [5] aspects of the protein folding problem. However, the matter is far from resolved, [6] remaining one of the great open problems of our time. [7] A complete understanding of the forces acting on individual amino acids during folding would undoubtedly enhance our understanding of this fundamental process.One of the more pivotal amino acids for protein folding and three-dimensional structure is glycine: H 2 NCH 2 COOH. Lacking a side chain, this residue is capable of adopting many conformations that are sterically challenging for amino acids with larger side chains. Theoretical investigations of glycine conformations have focused on isolated glycine molecules in the gas phase, [8] with most reports maintaining that hydrogen bonding between the amine and carboxylic acid moieties is responsible for the preferred gas-phase planar geometries.[8a, d-h, j] The conformational preferences of glycine in the context of a folded protein, on the other hand, have received far less attention. The original Ramachandran plot for glycine, based on hardsphere steric repulsions, suggested that most of the (f,y) conformational space apart from the two axes (f= 0, y = 0) should be available to glycine, [9] but as the number of determined high-resolution protein structures has grown, a clear bimodal distribution of preferred (f,y) conformations, characterized by y = 08 AE 508 and y = 1808 AE 608, has emerged (Figure 1). Ho and Brasseur have recently analysed the discrepancy between theoretical and actual glycine conformational density and concluded that this bimodal distribution is a result of steric clashes between glycine a H i atoms and nearby O i and N i+1 atoms. [10] Our interest in glycine stems from a little-heralded observation about the frequency of glycine-proline (Gly-Pro) pairings at the C termini (CT) of helices. Gunasekaran et al. report that out of the 318 helices ending with a glycine in a left-handed helical (a L ) conformation in their dataset, none was found to have a proline immediately following the capping glycine, despite proline's predominance in this second capping position.[11] The authors attributed this curious finding to the inability of proline to form an amide hydrogen bond characteristic of a L -capped helices.[11] These findings appear to be a special case of a more widespread phenomenon reported two decades ago, in which no glycine residues were found to adopt the a L conformation when followed by a proline, regardless of secondary structural environment. [12] This phenomenon was attributed to a steric clash between Gly NH and Pro d CH 2 atoms. [12] In this work we re-examine the conformational preferences of glycine and the instances of ...

The −BF–NH– Link as a Peptide-Bond Surrogate

“…Because full geometry optimization in this region makes possible a fine-tuning of the hydrogen-bond geometry, the γ-form is actually calculated to lie about 1 kcal/mol below that of the optimized β-form (see Table , left). A reverse effect applies in the α-helix region, around (−60/–40), where no extra-dipeptide hydrogen bonding is possible here, in contrast to widespread helicolidal polymers. , Nevertheless, this region forms a clear plateau lying at 3–4 kcal/mol above the extended minimum.…”

Conformational Preferences of Isolated Glycylglycine (Gly-Gly) Investigated with IRMPD-VUV Action Spectroscopy and Advanced Computational Approaches

“…By contrast, reduced steric hindrance, as revealed by the NCI analysis, contributes to its stability. Another plausible stabilization factor might be found in hyperconjugation effects, ,,, which are outside the scope of this study. In general, the obtained insight into the weak intramolecular hydrogen bonding in Gly-Gly structures might be of interest to studies of the interplay between intra- and intermolecular interactions ,− as well as cooperative and long-range effects in peptide structures. − …”

Protein folding, misfolding and aggregation: The importance of two-electron stabilizing interactions

“…When these two peptide bonds are approximately coplanar, φ i = −150°±30°, the situation is reversed. The generalized anomeric effect and homohyperconjugation are diminished due to vanishing overlap and the significance of the alternative hyperconjugative stabilization is limited [ 21 ] while the overlap for covalent contributions to backbone-backbone H-bonding is optimal [ 59 ]. The estimated energies Δ E (2) of the corresponding donor-acceptor interactions in the secondary structure models 1 - 5 , cf.…”

“…(1) The structure I contributes to the configuration of the least-polarized bonds which display positive r C = O vs. r C-N correlations [ 32 ], are relatively poor acceptors of H-bonds, form largely ionic backbone-backbone H-bonds [ 64 , 65 ], and are good π/resonance N lp donors; it is compatible with the PP II helix where backbone-backbone H-bonding is absent as well as the φ i = 180°±30°/ψ i = 180°±30° fold cf. Fig 1B(d) which is stabilized by the extended N lp hyperconjugation [ 21 ]. The least polarized backbone segment is therefore expected to exist as a statistical random coil unless molecular embedding turns it into an extended strand (the C 5 * strand) or a helix (PP II -helix or the α*-helix).…”