Dissertations, Theses, and Capstone Projects

Date of Degree

2-2026

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy

Program

Biochemistry

Advisor

Mateusz Marianski

Committee Members

Adam B. Braunschweig

Marilyn Gunner

Sharon M. Loverde

Jodi Hadden-Perilla

Subject Categories

Biochemistry | Chemistry | Computational Chemistry | Physical Sciences and Mathematics | Therapeutics

Keywords

Molecular Dynamics Simulations, Carbohydrates, Molecular Interactions, Carbohydrate Receptors, Therapeutics, Glycoproteins

Abstract

Carbohydrate oligomers play crucial roles in a variety of biological processes, including energy storage, intercellular communication, and the formation of structural polymers. The conformational dynamics of carbohydrates, which facilitates these diverse functions, is generally considered to be governed primarily by interactions between adjacent monomer units. As a first part of the thesis, I employ molecular dynamics simulations to investigate how interactions between non-adjacent monomers influence the overall structure of model oligosaccharides and N-glycans. In the second part of the thesis, I investigate a potential of targeting N-glycans for development of novel antiviral drugs. A deeper understanding of the role of long-range interactions in the structural organization and dynamics of carbohydrates will advance the development of new simulation techniques and force fields and will also enable practical applications such as the discovery of novel biomaterials and the design of innovative carbohydrate-binding drugs.

To quantify the impact of the interactions between non-adjacent monomers, I will use the difference between the conformational dynamics of a polymer and those of its disaccharide constituents, as reflected in the equilibrium distribution of glycosidic bond dihedral angles. I used CHARMM36 parameters to construct 384 unique structures of glucose, galactose, and mannose disaccharide and trisaccharide models and run molecular dynamics (MD) simulations for 500 ns each. The difference between the distribution of glycosidic bonds in trisaccharides and respective disaccharides was quantified using the Bhattacharyya distance function. Systematic analysis of different small oligomers show that some structures experience non-negligible differences in the equilibrium distribution of the glycosidic bonds, and the effect was most pronounced in branched oligosaccharides which have glycosidic bonds at neighboring positions and for 1 → 6 glycosidic linkages.

Next, we examined the impact of such long-range interactions between monosaccharides non-adjacent in sequence space in several biological systems: N-glycans, O-glycans, and lewis antigens. For the N-glycans system, I constructed 33 common N-glycans, as well as 16 disaccharides and 30 trisaccharides fragments. For the O-glycans system, I constructed 20 common O-glycans, and 20 disaccharide fragments. Finally, for lewis a and x I investigated 12 structures, and eleven constituting fragments. N-glycans, when compared to the di- and trisaccharide constituents, showed differences only for specific glycosidic bonds such as ω1-3 and ω1-6 glycosidic bond between mannose monosaccharides in the GlcNAc2Man3 pentasaccharide core, and in the presence of core fucosylation, bisecting GlcNAcs, and in the sialic-acid terminated antennae. The impact of long-range interactions in O-glycans, compared with disaccharides, was most pronounced for the β1 → 6 glycosidic bonds between GlcNAc and GalNAc, but was overall much smaller than other glycans. Finally, dynamics of lewis antigens experienced a significant deviations from the conformational equilibrium of its fragments, which highlights the signaling functions of these structures.

In the second part of the thesis, I examine the binding between ten Synthetic Carbohydrate Receptors (SCRs) and a library of more than 30 N-glycans and 20 O-glycans, some of which are common to viral proteins. To estimate the binding affinity between the SCR and N-glycan and O-glycan I monitored the distance between the two molecules throughout the simulation and used the ratio of the number of bound and unbound structures to calculate the association quotient. Analysis of the association quotient showed that some SCRs do not bind, some are promiscuous, and some are selective toward specific N-glycans, and they show very little binding towards O-glycans. Systematic variations in N-glycans, O-glycans and receptor structure would allow the search for and SCR design rules for the proposal of new receptors that could selectively bind to desired glycans. According to MD, it is possible for envelope glycans, which are currently considered “undruggable”, could become viable targets for new therapeutic strategies.

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