Dissecting the Conformational Stability of a Glycan Hairpin

Systematic structural studies of model oligopeptides revealed important aspects of protein folding and offered design principles to access non-natural materials. In the same way, the rules that regulate glycan folding could be established by studying synthetic oligosaccharide models. However, their analysis is often limited due to the synthetic and analytical complexity. By utilizing a glycan capable of spontaneously folding into a hairpin conformation as a model system, we investigated the factors that contribute to its conformational stability in aqueous solution. The modular design of the hairpin model featured a trisaccharide turn unit and two β-1,4-oligoglucoside stacking strands that allowed for systematic chemical modifications of the glycan sequence, including the introduction of NMR labels and staples. Nuclear magnetic resonance assisted by molecular dynamics simulations revealed that stereoelectronic effects and multiple glycan–glycan interactions are the major determinants of folding stabilization. Chemical modifications in the glycan primary sequence (e.g., strand elongation) can be employed to fine-tune the rigidity of structural motifs distant from the modification sites. These results could inspire the design of other glycan architectures, with implications in glycobiology and material sciences

Gauge copies in the Landau-DeWitt gauge: a background invariant restriction

The Landau background gauge, also known as the Landau-DeWitt gauge, has found renewed interest during the past decade given its usefulness in accessing the confinement-deconfinement transition via the vacuum expectation value of the Polyakov loop, describable via an appropriate background. In this Letter, we revisit this gauge from the viewpoint of it displaying gauge (Gribov) copies. We generalize the Gribov-Zwanziger effective action in a BRST and background invariant way; this action leads to a restriction on the allowed gauge fluctuations, thereby eliminating the infinitesimal background gauge copies. The explicit background invariance of our action is in contrast with earlier attempts to write down and use an effective Gribov-Zwanziger action. It allows to address certain subtleties arising in these earlier works, such as a spontaneous and thus spurious Lorentz symmetry breaking, something which is now averted.Comment: 14 pages. v2: version to appear in Phys.Lett.B, with minor modifications and extra reference

A nonlinear method of removing harmonic noise in geophysical data

A nonlinear, adaptive method to remove the harmonic noise that commonly resides in geophysical data is proposed in this study. This filtering method is based on the ensemble empirical mode decomposition algorithm in conjunction with the logarithmic transform. We present a synthetic model study to investigate the capability of signal reconstruction from the decomposed data, and compare the results with those derived from other 2-D adaptive filters. Applications to the real seismic data acquired by using an ocean bottom seismograph and to a shot gather of the ground penetrating radar demonstrate the robustness of this method. Our work proposes a concept that instead of Fourier-based approaches, the harmonic noise removal in geophysical data can be achieved effectively by using an alternative nonlinear adaptive data analysis method, which has been applied extensively in other scientific studies

Illuminating a Solvent-Dependent Hierarchy for Aromatic CH/π Complexes with Dynamic Covalent Glyco-Balances

CH/π interactions are prevalent among aromatic complexes and represent invaluable tools for stabilizing well-defined molecular architectures. Their energy contributions are exceptionally sensitive to various structural and environmental factors, resulting in a context-dependent nature that has led to conflicting findings in the scientific literature. Consequently, a universally accepted hierarchy for aromatic CH/π interactions has remained elusive. Herein, we present a comprehensive experimental investigation of aromatic CH/π complexes, employing a novel approach that involves isotopically labeled glyco-balances generated in situ. This innovative strategy not only allows us to uncover thermodynamic insights but also delves into the often less-accessible domain of kinetic information. Our analyses have yielded more than 180 new free energy values while considering key factors such as solvent properties, the interaction geometry, and the presence and nature of accompanying counterions. Remarkably, the obtained results challenge conventional wisdom regarding the stability order of common aromatic complexes. While it was believed that cationic CH/π interactions held the highest strength, followed by polarized CH/π, nonpolarized CH/π, and finally anionic CH/π interactions, our study reveals that this hierarchy can be subverted depending on the environment. Indeed, the performance of polarized CH/π interactions can match or even outcompete that of cationic CH/π interactions making them a more reliable stabilization strategy across the entire spectrum of solvent polarity. Overall, our results provide valuable guidelines for the selection of optimal interacting partners in every chemical environment, allowing the design of tailored aromatic complexes with applications in supramolecular chemistry, organocatalysis, and/or material sciences.This investigation was supported by research grants PID2019-107476GB-I00 and PID2022-141085NB-I00, funded by MCIN/AEI/10.13039/501100011033 and by ERDF A way of making Europe. A.G.S. is grateful for grant RYC2021-031704-I funded by MCIN/AEI/10.13039/501100011033 and by European Union NextGeneration EU/PRTR. L.D.-C. and A.V. respectively are grateful for grants BES-2017-080618 and PRE2020-093392, funded by MCIN/AEI/10.13039/501100011033 and by ESF Investing in your future, for a predoctoral contract each.Peer reviewe

Structural Modifications of Residual Lignins from Sisal and Flax Pulps during Soda-AQ Pulping and TCF/ECF Bleaching

We have studied the structural modifications of lignins from sisal and flax during their soda-anthraquinone (AQ) pulping and subsequent totally chlorine-free (TCF) and elementary chlorine-free (ECF) bleaching. For this purpose, residual lignins were isolated from pulps, analyzed by Py-GC/MS, 2D-NMR, and GPC, and their characteristics were compared to the “milled-wood” lignin of the raw materials. Soda-AQ pulping caused a preferential removal of S-lignin and cleavage of β–<i>O</i>–4′ linkages, but the structure of the residual lignin remained relatively similar to native lignin. TCF bleaching barely affected the lignin structure, and noticeable amounts of β–<i>O</i>–4′ linkages still occur in these pulps. In contrast, ECF bleaching caused strong modifications in the lignin structure with the complete removal of lignin markers in ECF-bleached sisal pulp. However, residual lignin was still present in ECF-bleached flax pulp, with a predominance of G- and H-lignin units and the presence of β–<i>O</i>–4′ linkages

Well-Defined Oligo- and Polysaccharides as Ideal Probes for Structural Studies

Polysaccharides are the most abundant organic materials in nature, yet correlations between their three-dimensional structure and macroscopic properties have not been established. Automated glycan assembly enables the preparation of well-defined oligo- and polysaccharides resembling natural as well as unnatural structures. These synthetic glycans are ideal probes for the fundamental study of polysaccharides. According to molecular modeling simulations and NMR analysis, different classes of polysaccharides adopt fundamentally different conformations that are drastically altered by single-site substitutions. Larger synthetic polysaccharides are obtained via a “LEGO”-like approach as a first step toward the production of tailor-made carbohydrate-based materials

Well-Defined Oligo- and Polysaccharides as Ideal Probes for Structural Studies

Polysaccharides are the most abundant organic materials in nature, yet correlations between their three-dimensional structure and macroscopic properties have not been established. Automated glycan assembly enables the preparation of well-defined oligo- and polysaccharides resembling natural as well as unnatural structures. These synthetic glycans are ideal probes for the fundamental study of polysaccharides. According to molecular modeling simulations and NMR analysis, different classes of polysaccharides adopt fundamentally different conformations that are drastically altered by single-site substitutions. Larger synthetic polysaccharides are obtained via a “LEGO”-like approach as a first step toward the production of tailor-made carbohydrate-based materials

Water Sculpts the Distinctive Shapes and Dynamics of the Tumor-Associated Carbohydrate Tn Antigens: Implications for Their Molecular Recognition

The tumor-associated carbohydrate Tn antigens include two variants, αGalNAc-<i>O</i>-Thr and αGalNAc-<i>O</i>-Ser. In solution, they exhibit dissimilar shapes and dynamics and bind differently to the same protein receptor. Here, we demonstrate experimentally and theoretically that their conformational preferences in the gas phase are highly similar, revealing the essential role of water. We propose that water molecules prompt the rotation around the glycosidic linkage in the threonine derivative, shielding its hydrophobic methyl group and allowing an optimal solvation of the polar region of the antigen. The unusual arrangement of αGalNAc-<i>O</i>-Thr features a water molecule bound into a “pocket” between the sugar and the threonine. This mechanism is supported by trapping, for the first time, such localized water in the crystal structures of an antibody bound to two glycopeptides that comprise fluorinated Tn antigens in their structure. According to several reported X-ray structures, installing oxygenated amino acids in specific regions of the receptor capable of displacing the bridging water molecule to the bulk-solvent may facilitate the molecular recognition of the Tn antigen with threonine. Overall, our data also explain how water fine-tunes the 3D structure features of similar molecules, which in turn are behind their distinct biological activities

Well-Defined Oligo- and Polysaccharides as Ideal Probes for Structural Studies

Polysaccharides are the most abundant organic materials in nature, yet correlations between their three-dimensional structure and macroscopic properties have not been established. Automated glycan assembly enables the preparation of well-defined oligo- and polysaccharides resembling natural as well as unnatural structures. These synthetic glycans are ideal probes for the fundamental study of polysaccharides. According to molecular modeling simulations and NMR analysis, different classes of polysaccharides adopt fundamentally different conformations that are drastically altered by single-site substitutions. Larger synthetic polysaccharides are obtained via a “LEGO”-like approach as a first step toward the production of tailor-made carbohydrate-based materials

Design of α‑<i>S</i>‑Neoglycopeptides Derived from MUC1 with a Flexible and Solvent-Exposed Sugar Moiety

The use of vaccines based on MUC1 glycopeptides is a promising approach to treat cancer. We present herein several sulfa-Tn antigens incorporated in MUC1 sequences that possess a variable linker between the carbohydrate (GalNAc) and the peptide backbone. The main conformations of these molecules in solution have been evaluated by combining NMR experiments and molecular dynamics simulations. The linker plays a key role in the modulation of the conformation of these compounds at different levels, blocking a direct contact between the sugar moiety and the backbone, promoting a helix-like conformation for the glycosylated residue and favoring the proper presentation of the sugar unit for molecular recognition events. The feasibility of these novel compounds as mimics of MUC1 antigens has been validated by the X-ray diffraction structure of one of these unnatural derivatives complexed to an anti-MUC1 monoclonal antibody. These features, together with potential lack of immune suppression, render these unnatural glycopeptides promising candidates for designing alternative therapeutic vaccines against cancer