Glycosylation Modulates the Structure and Functions of Collagen: A Review.

Collagens are fundamental constituents of the extracellular matrix and are the most abundant proteins in mammals. Collagens belong to the family of fibrous or fiber-forming proteins that self-assemble into fibrils that define their mechanical properties and biological functions. Up to now, 28 members of the collagen superfamily have been recognized.

How E-, L-, and P-Selectins Bind to sLe and PSGL-1: A Quantification of Critical Residue Interactions.

Selectins and their ability to interact with specific ligands are a cornerstone in cell communication. Over the last three decades, a considerable wealth of experimental and molecular modeling insights into their structure and were gathered. Nonetheless, explaining the role of individual selectin residues on a quantitative level remained elusive, despite its importance in understanding the structure-function relationship in these molecules and designing their inhibitors.

Molecular Modeling Insights into the Structure and Behavior of Integrins: A Review.

Integrins are heterodimeric glycoproteins crucial to the physiology and pathology of many biological functions. As adhesion molecules, they mediate immune cell trafficking, migration, and immunological synapse formation during inflammation and cancer. The recognition of the vital roles of integrins in various diseases revealed their therapeutic potential.

The catalytic reaction mechanism of tyrosylprotein sulfotransferase-1.

Tyrosine sulfation alters the biological activity of many proteins involved in different physiological and pathophysiological conditions, such as non-specific immune reaction, response to inflammation and ischemia, targeting of leukocytes and stem cells, or the formation of cancer metastases. Tyrosine sulfation is catalyzed by the enzymes tyrosylprotein sulfotransferases (TPST). In this study, we used QM/MM Car-Parrinello metadynamics simulations together with QM/MM potential energy calculations to investigate the catalytic mechanism of isoform TPST-1.

Pan-selectin inhibitors as potential therapeutics for COVID-19 treatment: in silico screening study.

Coronavirus disease 2019 (COVID-19) has spread rapidly throughout the globe. The spectrum of disease is broad but among hospitalized patients with COVID-19, respiratory failure from acute respiratory distress syndrome is the leading cause of mortality. There is an urgent need for an effective treatment.

Catalytic Mechanism of Processive GlfT2: Transition Path Sampling Investigation of Substrate Translocation.

We applied the transition path sampling (TPS) method to study the translocation step of the catalytic mechanism of galactofuranosyl transferase 2 (GlfT2). Using TPS in the field of enzymatic reactions is still relatively rare, and we show its effectiveness on this enzymatic system. We decipher an unknown mechanism of the translocation step and, thus, provide a complete understanding of the catalytic mechanism of GlfT2 at the atomistic level.

Selectins-The Two Dr. Jekyll and Mr. Hyde Faces of Adhesion Molecules-A Review.

Selectins belong to a group of adhesion molecules that fulfill an essential role in immune and inflammatory responses and tissue healing. Selectins are glycoproteins that decode the information carried by glycan structures, and non-covalent interactions of selectins with these glycan structures mediate biological processes. The sialylated and fucosylated tetrasaccharide sLe is an essential glycan recognized by selectins.

Atomistic simulation of carbohydrate-protein complex formation: Hevein-32 domain.

Interactions between proteins and their small molecule ligands are of great importance for the process of drug design. Here we report an unbiased molecular dynamics simulation of systems containing hevein domain (HEV32) with N-acetylglucosamine mono-, di- or trisaccharide. Carbohydrate molecules were placed outside the binding site.

Discovery of processive catalysis by an exo-hydrolase with a pocket-shaped active site.

Substrates associate and products dissociate from enzyme catalytic sites rapidly, which hampers investigations of their trajectories. The high-resolution structure of the native Hordeum exo-hydrolase HvExoI isolated from seedlings reveals that non-covalently trapped glucose forms a stable enzyme-product complex. Here, we report that the alkyl β-D-glucoside and methyl 6-thio-β-gentiobioside substrate analogues perfused in crystalline HvExoI bind across the catalytic site after they displace glucose, while methyl 2-thio-β-sophoroside attaches nearby.

How Mycobacterium tuberculosis Galactofuranosyl Transferase 2 (GlfT2) Generates Alternating β-(1-6) and β-(1-5) Linkages: A QM/MM Molecular Dynamics Study of the Chemical Steps.

Mycobacterium tuberculosis features a unique cell wall that protects the bacterium from the external environment. Disruption of the cell wall assembly is a promising direction for novel anti-tuberculotic drugs. A key component of the cell wall is galactan, a polysaccharide chain composed of galactofuranose (Galf) units connected by alternating β-(1-5) and β-(1-6) linkages.

Automated Training of ReaxFF Reactive Force Fields for Energetics of Enzymatic Reactions.

Computational studies of the reaction mechanisms of various enzymes are nowadays based almost exclusively on hybrid QM/MM models. Unfortunately, the success of this approach strongly depends on the selection of the QM region, and computational cost is a crucial limiting factor. An interesting alternative is offered by empirical reactive molecular force fields, especially the ReaxFF potential developed by van Duin and co-workers.

First-Principles Interaction Analysis Assessment of the Manganese Cation in the Catalytic Activity of Glycosyltransferases.

The energetic effect of water substitution reactions in hexacoordinated [Mn(HO)L] complexes with L = methanol, formic acid, formamide, formate, imidazole, and diphosphate is quantitatively analyzed at the MP2/triple-ζ level of theory. Subsequently, the state-of-the-art open shell symmetry-adapted perturbation theory (SAPT) analysis of the interaction energies of Mn···ligand dimers with selected O-, S-, and N-binding ligands is presented and compared to similar interactions of Mg and Zn ions. We find that the induction energies in the dimers with manganese are almost twice as large as in dimers with magnesium.

Different QM/MM Approaches To Elucidate Enzymatic Reactions: Case Study on ppGalNAcT2.

Hybrid QM/MM computational studies can provide invaluable insight into the mechanisms of enzymatic reactions that can be exploited for rational drug design. Various approaches are available for such studies. However, their strengths and weaknesses may not be immediately apparent.

Using DFT methodology for more reliable predictive models: Design of inhibitors of Golgi α-Mannosidase II.

Human Golgi α-mannosidase II (GMII), a zinc ion co-factor dependent glycoside hydrolase (E.C.3.

Three-dimensional homology model of GlcNAc-TV glycosyltransferase.

The enzyme UDP-N-acetylglucosamine: α-d-mannoside β-1-6 N-acetylglucosaminyltransferase V (GnT-V) catalyzes the transfer of GlcNAc from the UDP-GlcNAc donor to the α-1-6-linked mannose of the trimannosyl core structure of glycoproteins to produce the β-1-6-linked branching of N-linked oligosaccharides. β-1-6-GlcNAc-branched N-glycans are associated with cancer growth and metastasis. Therefore, the inhibition of GnT-V represents a key target for anti-cancer drug development.

Ab initio modelling of the anomeric and exo anomeric effects in 2-methoxytetrahydropyran and 2-methoxythiane corrected for intramolecular BSSE.

Accurate ab initio calculations including basis set limit (BSL) extrapolations, removal of intramolecular basis set superposition error (BSSE), solvent effect corrections, and thermal effects have been carried out to compare the structure and the anomeric and exo-anomeric effect in 2-methoxytetrahydropyran and 2-methoxythiane. The effect of intramolecular BSSE on the energetics was outlined for the first time in these types of compounds. It was found that both title compounds show comparable behaviour with respect to BSSE.

Stepwise catalytic mechanism via short-lived intermediate inferred from combined QM/MM MERP and PES calculations on retaining glycosyltransferase ppGalNAcT2.

The glycosylation of cell surface proteins plays a crucial role in a multitude of biological processes, such as cell adhesion and recognition. To understand the process of protein glycosylation, the reaction mechanisms of the participating enzymes need to be known. However, the reaction mechanism of retaining glycosyltransferases has not yet been sufficiently explained.

Molecular simulations of hevein/(GlcNAc)3 complex with weakened OH/O and CH/π hydrogen bonds: implications for their role in complex stabilization.

Carbohydrate-protein complexes are often characterized by interactions via aromatic amino acid residues. Several mechanisms have been proposed to explain these stacking-like interactions between pyranose sugars and aromatic moieties. The physical basis of these interactions is being explained as either dispersion CH/π or hydrophobic.

QM/MM methods for studying enzymatic reactions of glycosyltransferases.

Hybrid quantum mechanics and molecular mechanics (QM/MM) methods have become a powerful tool to provide an accurate and effective description of complex biological systems. The QM treatment of the electronic structure of an active site region and the rest of the enzyme by molecular mechanics allows enzymatic reaction to being modeled with including the impact of environment. Different reaction pathways of the enzymatic mechanism can be tested--transition states (TS) and intermediates characterized using QM/MM methods, leading to significant advances in understanding enzymatic reactions.

Exploring reaction pathways for O-GlcNAc transferase catalysis. A string method study.

The inverting O-GlcNAc glycosyltransferase (OGT) is an important post-translation enzyme, which catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine (UDP-GlcNAc) to the hydroxyl group of the Ser/Thr of cytoplasmic, nuclear, and mitochondrial proteins. In the past, three different catalytic bases were proposed for the reaction: His498, α-phosphate, and Asp554. In this study, we used hybrid quantum mechanics/molecular mechanics (QM/MM) Car-Parrinello molecular dynamics to investigate reaction paths using α-phosphate and Asp554 as the catalytic bases.

Carbohydrate-protein interactions: molecular modeling insights.

The article reviews the significant contributions to, and the present status of, applications of computational methods for the characterization and prediction of protein-carbohydrate interactions. After a presentation of the specific features of carbohydrate modeling, along with a brief description of the experimental data and general features of carbohydrate-protein interactions, the survey provides a thorough coverage of the available computational methods and tools. At the quantum-mechanical level, the use of both molecular orbitals and density-functional theory is critically assessed.

Theoretical study of enzymatic catalysis explains why the trapped covalent intermediate in the E303C mutant of glycosyltransferase GTB was not detected in the wild-type enzyme.

Hybrid quantum mechanics/molecular mechanics calculations were used to study the catalytic mechanism of the retaining human α-(1,3)-galactosyltransferase (GTBWT) and its E303C mutant (GTBE303C). Both backside (via covalent glycosyl-enzyme intermediate, CGEI) and frontside SNi-like mechanisms (via oxocarbenium-ion intermediate, OCII) were investigated. The calculations suggest that both mechanisms are feasible in the enzymatic catalysis.

Atomistic insight into the catalytic mechanism of glycosyltransferases by combined quantum mechanics/molecular mechanics (QM/MM) methods.

Glycosyltransferases catalyze the formation of glycosidic bonds by assisting the transfer of a sugar residue from donors to specific acceptor molecules. Although structural and kinetic data have provided insight into mechanistic strategies employed by these enzymes, molecular modeling studies are essential for the understanding of glycosyltransferase catalyzed reactions at the atomistic level. For such modeling, combined quantum mechanics/molecular mechanics (QM/MM) methods have emerged as crucial.

A theoretical study on the catalytic mechanism of the retaining α-1,2-mannosyltransferase Kre2p/Mnt1p: the impact of different metal ions on catalysis.

Glycosyltransferases are sugar-processing enzymes that require a specific metal ion cofactor for catalysis. In the presence of other ions the catalysis is often impaired. Here, for the first time, the enzymatic catalysis in the presence of various metal ions was modeled for a glycosyltransferase using a large enzymatic model.

A QM/MM investigation of the catalytic mechanism of metal-ion-independent core 2 β1,6-N-acetylglucosaminyltransferase.

β1,6-GlcNAc-transferase (C2GnT) is an important controlling factor of biological functions for many glycoproteins and its activity has been found to be altered in breast, colon, and lung cancer cells, in leukemia cells, in the lymhomonocytes of multiple sclerosis patients, leukocytes from diabetes patients, and in conditions causing an immune deficiency. The result of the action of C2GnT is the core 2 structure that is essential for the further elongation of the carbohydrate chains of O-glycans. The catalytic mechanism of this metal-ion-independent glycosyltransferase is of paramount importance and is investigated here by using quantum mechanical (QM) (density functional theory (DFT))/molecular modeling (MM) methods with different levels of theory.