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Conformational Dynamics and Exchange Kinetics of N-Formyl and N-Acetyl Groups Substituting 3-Amino-3,6-dideoxy-alpha-D-galactopyranose, a Sugar Found in Bacterial O-Antigen Polysaccharides
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.ORCID-id: 0000-0001-5657-8635
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.ORCID-id: 0000-0001-8303-4481
2017 (Engelska)Ingår i: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 121, nr 41, s. 9487-9497Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Three dimensional shape and conformation of. carbohydrates are important factors in molecular recognition events and the N-acetyl group of a monosaccharide residue can function as a conformational gatekeeper whereby it influences the overall shape of the oligosaccharide. NMR spectroscopy and quantum mechanics (QM) calculations are used herein to investigate both the conformational preferences and the dynamic behavior of N-acetyl and N-formyl substituents of 3-amino-3,6-dideoxy-alpha-D-galactopyranose, a sugar and substitution pattern found in bacterial O-antigen polysaccharides. QM calculations suggest that the amide oxygen can be involved in hydrogen bonding with the axial OH4 group primarily but also with the equatorial OH2 group. However, an NMR J coupling analysis indicates that the 01 torsion angle, adjacent to the sugar ring, prefers an ap conformation where conformations <180 degrees also are accessible, but does not allow for intramolecular hydrogen bonding. In the formyl-substituted compound (4)J(HH) coupling constants to the exo-cyclic group were detected and analyzed. A van't Hoff analysis revealed that the trans conformation at the amide bond is favored by Delta G degrees approximate to - 0.8 kcal.mol(-1) in the formyl-containing compound and with Delta G degrees approximate to -2.5 kcal.mol(-1) when the N-acetyl group is the substituent. In both cases the enthalpic term dominates to the free energy, irrespective of water or DMSO as solvent, with only a small contribution from the entropic term. The cis-trans isomerization of the theta(2) torsion angle, centered at the amide bond, was also investigated by employing H-1 NMR line shape analysis and C-13 NMR saturation transfer experiments. The extracted transition rate constants were utilized to calculate transition energy barriers that were found to be about 20 kcal.mol(-1) in both DMSO-d(6) and D2O. Enthalpy had a higher contribution to the energy barriers in DMSO-d(6) compared to in D2O, where entropy compensated for the loss of enthalpy.

Ort, förlag, år, upplaga, sidor
American Chemical Society (ACS), 2017. Vol. 121, nr 41, s. 9487-9497
Nationell ämneskategori
Organisk kemi
Forskningsämne
organisk kemi
Identifikatorer
URN: urn:nbn:se:su:diva-148998DOI: 10.1021/acs.jpcb.7b05611ISI: 000413617800001PubMedID: 28933544OAI: oai:DiVA.org:su-148998DiVA, id: diva2:1160552
Forskningsfinansiär
VetenskapsrådetKnut och Alice Wallenbergs Stiftelse
Anmärkning

Open Access 2019-12-01

Tillgänglig från: 2017-11-27 Skapad: 2017-11-27 Senast uppdaterad: 2019-09-06Bibliografiskt granskad
Ingår i avhandling
1. Exploring the Molecular Behavior of Carbohydrates by NMR Spectroscopy: Shapes, motions and interactions
Öppna denna publikation i ny flik eller fönster >>Exploring the Molecular Behavior of Carbohydrates by NMR Spectroscopy: Shapes, motions and interactions
2015 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Carbohydrates are essential biomolecules that decorate cell membranes and proteins in organisms. They are important both as structural elements and as identification markers. Many biological and pathogenic processes rely on the identification of carbohydrates by proteins, thereby making them attractive as molecular blueprints for drugs. This thesis describes how NMR spectroscopy can be utilized to study carbohydrates in solution at a molecular level. This versatile technique facilitates for investigations of (i) shapes, (ii) motions and (iii) interactions.

A conformational study of an E. coli O-antigen was performed by calculating atomic distances from NMR NOESY experiments. The acquired data was utilized to validate MD simulations of the LPS embedded in a membrane. The agreement between experimental and calculated data was good and deviations were proven to arise from spin-diffusion. In another study presented herein, both the conformation and the dynamic behavior of amide side-chains linked to derivatives of D-Fucp3N, a sugar found in the O-antigen of bacteria, were investigated. J-couplings facilitated a conformational analysis and 13C saturation transfer NMR experiments were utilized to measure rate constants of amide cis-trans isomerizations.

13C NMR relaxation and 1H PFG diffusion measurements were carried out to explore and describe the molecular motion of mannofullerenes. The dominating motions of the mannofullerene spectral density were found to be related to pulsating motions of the linkers rather than global rotational diffusion. The promising inhibition of Ebola viruses identified for a larger mannofullerene can thus be explained by an efficient rebinding mechanism that arises from the observed flexibility in the linker.

Molecular interactions between sugars and caffeine in water were studied by monitoring chemical shift displacements in titrations. The magnitude of the chemical shift displacements indicate that the binding occurs by a face to face stacking of the aromatic plane of caffeine to the ring plane of the sugar, and that the interaction is at least partly driven by solvation effects. Also, the binding of a Shigella flexneri serotype Y octasaccharide to a bacteriophage Sf6 tail spike protein was investigated. This interaction was studied by 1H STD NMR and trNOESY experiments. A quantitative analysis of the STD data was performed employing a newly developed method, CORCEMA-ST-CSD, that is able to simulate STD data more accurately since the line broadening of protein resonances are accounted for in the calculations.

Ort, förlag, år, upplaga, sidor
Stockholm: Department of Organic Chemistry, Stockholm University, 2015
Nyckelord
NMR spectroscopy, NMR relaxation, DNMR, CORCEMA-ST, carbohydrates, caffeine, O-antigen, glycofullerenes
Nationell ämneskategori
Organisk kemi
Forskningsämne
organisk kemi
Identifikatorer
urn:nbn:se:su:diva-116037 (URN)978-91-7649-140-9 (ISBN)
Disputation
2015-05-22, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (Engelska)
Opponent
Handledare
Forskningsfinansiär
Vetenskapsrådet
Anmärkning

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 4: Manuscript. Paper 5: Manuscript.

Tillgänglig från: 2015-04-29 Skapad: 2015-04-09 Senast uppdaterad: 2018-03-27Bibliografiskt granskad
2. Synthesis and analysis of carbohydrates related to bacterial polysaccharides
Öppna denna publikation i ny flik eller fönster >>Synthesis and analysis of carbohydrates related to bacterial polysaccharides
2018 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The outer surface of bacteria is composed of around 75% carbohydrates, which are vital for the bacteria to survive and communicate with the host biological system. The thesis discusses different properties of carbohydrates that are essential for understanding the bacterial behavior in biological systems. The first three chapters give an overview of carbohydrates.

The fourth chapter discusses the synthesis of four amide-substituted 3,6-dideoxy-α-D-galactopyranosides, namely, methyl α-3,6-dideoxy-3-formamido-, acetamido-, (R)-3-hydroxybutyramido-, and (4-hydroxybutyramido)-D-galactopyranoside. These sugars were found as components of some bacterial O-antigens; the study is a step toward the synthesis of oligosaccharides that contain them. The fifth chapter describes the exchange kinetics of the formyl and acetyl derivatives that were synthesized. Both of them have two conformational states for the amide side-chain. 13C-NMR saturation transfer experiments are utilized for these measurements to reveal more about their properties in solution.

In chaptr six, NMR and conformational analysis of oligosaccharides related to the O-antigen of Yersinia enterocolitica O:3 bacteria were carried out to obtain more information regarding their 3D structure.

Chapter seven is focusing on the development of CASPER, a program for rapid assignment of 1H- and 13C-NMR chemical shifts of bacterial lipopolysaccharides, by adding more sugars into its database and testing it for naturally occurring LPS as well as extending the scope for synthetic carbohydrates, which is planned to be developed further in the future.

Ort, förlag, år, upplaga, sidor
Stockholm: Department of Organic Chemistry, Stockholm University, 2018. s. 53
Nyckelord
carbohydrates, synthesis, conformation, NMR, O-antigen, computer-assisted structure elucidation
Nationell ämneskategori
Organisk kemi
Forskningsämne
organisk kemi
Identifikatorer
urn:nbn:se:su:diva-154449 (URN)978-91-7797-216-7 (ISBN)978-91-7797-217-4 (ISBN)
Disputation
2018-05-15, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (Engelska)
Opponent
Handledare
Anmärkning

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

Tillgänglig från: 2018-04-20 Skapad: 2018-03-27 Senast uppdaterad: 2018-04-23Bibliografiskt granskad

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