Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Molecular simulations of carbohydrates and protein-carbohydrate interactions: motivation, issues and prospects.

ABSTRACT: The characterization of the 3D structure of oligosaccharides, their conjugates and analogs is particularly challenging for traditional experimental methods. Molecular simulation methods provide a basis for interpreting sparse experimental data and for independently predicting conformational and dynamic properties of glycans. Here, we summarize and analyze the issues associated with modeling carbohydrates, with a detailed discussion of four of the most recently developed carbohydrate force fields, reviewed in terms of applicability to natural glycans, carbohydrate-protein complexes and the emerging area of glycomimetic drugs. In addition, we discuss prospectives and new applications of carbohydrate modeling in drug discovery.

SUBMITTER: Fadda E

PROVIDER: S-EPMC3936463 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Molecular simulations of carbohydrates and protein-carbohydrate interactions: motivation, issues and prospects.

Fadda Elisa E Woods Robert J RJ

Drug discovery today 20100608 15-16

The characterization of the 3D structure of oligosaccharides, their conjugates and analogs is particularly challenging for traditional experimental methods. Molecular simulation methods provide a basis for interpreting sparse experimental data and for independently predicting conformational and dynamic properties of glycans. Here, we summarize and analyze the issues associated with modeling carbohydrates, with a detailed discussion of four of the most recently developed carbohydrate force fields ...[more]

PMID: 20594934

Similar Datasets

Quantifying Protein-Protein Interactions in Molecular Simulations.

Project description:Interactions among proteins, nucleic acids, and other macromolecules are essential for their biological functions and shape the physicochemcial properties of the crowded environments inside living cells. Binding interactions are commonly quantified by dissociation constants Kd, and both binding and nonbinding interactions are quantified by second osmotic virial coefficients B2. As a measure of nonspecific binding and stickiness, B2 is receiving renewed attention in the context of so-called liquid-liquid phase separation in protein and nucleic acid solutions. We show that Kd is fully determined by B2 and the fraction of the dimer observed in molecular simulations of two proteins in a box. We derive two methods to calculate B2. From molecular dynamics or Monte Carlo simulations using implicit solvents, we can determine B2 from insertion and removal energies by applying Bennett's acceptance ratio (BAR) method or the (binless) weighted histogram analysis method (WHAM). From simulations using implicit or explicit solvents, one can estimate B2 from the probability that the two molecules are within a volume large enough to cover their range of interactions. We validate these methods for coarse-grained Monte Carlo simulations of three weakly binding proteins. Our estimates for Kd and B2 allow us to separate out the contributions of nonbinding interactions to B2. Comparison of calculated and measured values of Kd and B2 can be used to (re-)parameterize and improve molecular force fields by calibrating specific affinities, overall stickiness, and nonbinding interactions. The accuracy and efficiency of Kd and B2 calculations make them well suited for high-throughput studies of large interactomes.

| S-EPMC7294537 | biostudies-literature

Exploiting Uniformly <sup>13</sup>C-Labeled Carbohydrates for Probing Carbohydrate-Protein Interactions by NMR Spectroscopy.

Project description:NMR of a uniformly 13C-labeled carbohydrate was used to elucidate the atomic details of a sugar-protein complex. The structure of the 13C-labeled Manα(1-2)Manα(1-2)ManαOMe trisaccharide ligand, when bound to cyanovirin-N (CV-N), was characterized and revealed that in the complex the glycosidic linkage torsion angles between the two reducing-end mannoses are different from the free trisaccharide. Distances within the carbohydrate were employed for conformational analysis, and NOE-based distance mapping between sugar and protein revealed that Manα(1-2)Manα(1-2)ManαOMe is bound more intimately with its two reducing-end mannoses into the domain A binding site of CV-N than with the nonreducing end unit. Taking advantage of the 13C spectral dispersion of 13C-labeled carbohydrates in isotope-filtered experiments is a versatile means for a simultaneous mapping of the binding interactions on both, the carbohydrate and the protein.

| S-EPMC5725960 | biostudies-literature

Protein-Protein Interactions: Insight from Molecular Dynamics Simulations and Nanoparticle Tracking Analysis.

Project description:Protein-protein interaction plays an essential role in almost all cellular processes and biological functions. Coupling molecular dynamics (MD) simulations and nanoparticle tracking analysis (NTA) assay offered a simple, rapid, and direct approach in monitoring the protein-protein binding process and predicting the binding affinity. Our case study of designed ankyrin repeats proteins (DARPins)-AnkGAG1D4 and the single point mutated AnkGAG1D4-Y56A for HIV-1 capsid protein (CA) were investigated. As reported, AnkGAG1D4 bound with CA for inhibitory activity; however, it lost its inhibitory strength when tyrosine at residue 56 AnkGAG1D4, the most key residue was replaced by alanine (AnkGAG1D4-Y56A). Through NTA, the binding of DARPins and CA was measured by monitoring the increment of the hydrodynamic radius of the AnkGAG1D4-gold conjugated nanoparticles (AnkGAG1D4-GNP) and AnkGAG1D4-Y56A-GNP upon interaction with CA in buffer solution. The size of the AnkGAG1D4-GNP increased when it interacted with CA but not AnkGAG1D4-Y56A-GNP. In addition, a much higher binding free energy (∆GB) of AnkGAG1D4-Y56A (-31 kcal/mol) obtained from MD further suggested affinity for CA completely reduced compared to AnkGAG1D4 (-60 kcal/mol). The possible mechanism of the protein-protein binding was explored in detail by decomposing the binding free energy for crucial residues identification and hydrogen bond analysis.

| S-EPMC8472368 | biostudies-literature

The energetics of protein-lipid interactions as viewed by molecular simulations.

Project description:Membranes are formed from a bilayer containing diverse lipid species with which membrane proteins interact. Integral, membrane proteins are embedded in this bilayer, where they interact with lipids from their surroundings, whilst peripheral membrane proteins bind to lipids at the surface of membranes. Lipid interactions can influence the function of membrane proteins, either directly or allosterically. Both experimental (structural) and computational approaches can reveal lipid binding sites on membrane proteins. It is, therefore, important to understand the free energies of these interactions. This affords a more complete view of the engagement of a particular protein with the biological membrane surrounding it. Here, we describe many computational approaches currently in use for this purpose, including recent advances using both free energy and unbiased simulation methods. In particular, we focus on interactions of integral membrane proteins with cholesterol, and with anionic lipids such as phosphatidylinositol 4,5-bis-phosphate and cardiolipin. Peripheral membrane proteins are exemplified via interactions of PH domains with phosphoinositide-containing membranes. We summarise the current state of the field and provide an outlook on likely future directions of investigation.

| S-EPMC7054751 | biostudies-literature

Relative Affinities of Protein-Cholesterol Interactions from Equilibrium Molecular Dynamics Simulations.

Project description:Specific interactions of lipids with membrane proteins contribute to protein stability and function. Multiple lipid interactions surrounding a membrane protein are often identified in molecular dynamics (MD) simulations and are, increasingly, resolved in cryo-electron microscopy (cryo-EM) densities. Determining the relative importance of specific interaction sites is aided by determination of lipid binding affinities using experimental or simulation methods. Here, we develop a method for determining protein-lipid binding affinities from equilibrium coarse-grained MD simulations using binding saturation curves, designed to mimic experimental protocols. We apply this method to directly obtain affinities for cholesterol binding to multiple sites on a range of membrane proteins and compare our results with free energies obtained from density-based equilibrium methods and with potential of mean force calculations, getting good agreement with respect to the ranking of affinities for different sites. Thus, our binding saturation method provides a robust, high-throughput alternative for determining the relative consequence of individual sites seen in, e.g., cryo-EM derived membrane protein structures surrounded by an array of ancillary lipid densities.

| S-EPMC8515805 | biostudies-literature

Exploring multivalent carbohydrate-protein interactions by NMR.

Project description:Nuclear Magnetic Resonance (NMR) has been widely employed to assess diverse features of glycan-protein molecular recognition events. Different types of qualitative and quantitative information at different degrees of resolution and complexity can be extracted from the proper application of the available NMR-techniques. In fact, affinity, structural, kinetic, conformational, and dynamic characteristics of the binding process are available. Nevertheless, except in particular cases, the affinity of lectin-sugar interactions is weak, mostly at the low mM range. This feature is overcome in biological processes by using multivalency, thus augmenting the strength of the binding. However, the application of NMR methods to monitor multivalent lectin-glycan interactions is intrinsically challenging. It is well known that when large macromolecular complexes are formed, the NMR signals disappear from the NMR spectrum, due to the existence of fast transverse relaxation, related to the large size and exchange features. Indeed, at the heart of the molecular recognition event, the associated free-bound chemical exchange process for both partners takes place in a particular timescale. Thus, these factors have to be considered and overcome. In this review article, we have distinguished, in a subjective manner, the existence of multivalent presentations in the glycan or in the lectin. From the glycan perspective, we have also considered whether multiple epitopes of a given ligand are presented in the same linear chain of a saccharide (i.e., poly-LacNAc oligosaccharides) or decorating different arms of a multiantennae scaffold, either natural (as in multiantennae N-glycans) or synthetic (of dendrimer or polymer nature). From the lectin perspective, the presence of an individual binding site at every monomer of a multimeric lectin may also have key consequences for the binding event at different levels of complexity.

| S-EPMC9987413 | biostudies-literature

Dynamic fluctuations of protein-carbohydrate interactions promote protein aggregation.

Project description:Protein-carbohydrate interactions are important for glycoprotein structure and function. Antibodies of the IgG class, with increasing significance as therapeutics, are glycosylated at a conserved site in the constant Fc region. We hypothesized that disruption of protein-carbohydrate interactions in the glycosylated domain of antibodies leads to the exposure of aggregation-prone motifs. Aggregation is one of the main problems in protein-based therapeutics because of immunogenicity concerns and decreased efficacy. To explore the significance of intramolecular interactions between aromatic amino acids and carbohydrates in the IgG glycosylated domain, we utilized computer simulations, fluorescence analysis, and site-directed mutagenesis. We find that the surface exposure of one aromatic amino acid increases due to dynamic fluctuations. Moreover, protein-carbohydrate interactions decrease upon stress, while protein-protein and carbohydrate-carbohydrate interactions increase. Substitution of the carbohydrate-interacting aromatic amino acids with non-aromatic residues leads to a significantly lower stability than wild type, and to compromised binding to Fc receptors. Our results support a mechanism for antibody aggregation via decreased protein-carbohydrate interactions, leading to the exposure of aggregation-prone regions, and to aggregation.

| S-EPMC2791859 | biostudies-literature

Carbohydrate-protein recognition: molecular dynamics simulations and free energy analysis of oligosaccharide binding to concanavalin A.

Project description:Carbohydrate ligands are important mediators of biomolecular recognition. Microcalorimetry has found the complex-type N-linked glycan core pentasaccharide beta-GlcNAc-(1-->2)-alpha-Man-(1-->3)-[beta-GlcNAc-(1-->2)-alpha-Man-(1-->6)]-Man to bind to the lectin, Concanavalin A, with almost the same affinity as the trimannoside, Man-alpha-(1-->6)-[Man-alpha-(1-->3)]-Man. Recent determination of the structure of the pentasaccharide complex found a glycosidic linkage psi torsion angle to be distorted by 50 degrees from the NMR solution value and perturbation of some key mannose-protein interactions observed in the structures of the mono- and trimannoside complexes. To unravel the free energy contributions to binding and to determine the structural basis for this degeneracy, we present the results of a series of nanosecond molecular dynamics simulations, coupled to analysis via the recently developed MM-GB/SA approach (Srinivasan et al., J. Am. Chem. Soc. 1998, 120:9401-9409). These calculations indicate that the strength of key mannose-protein interactions at the monosaccharide site is preserved in both the oligosaccharides. Although distortion of the pentasaccharide is significant, the principal factor in reduced binding is incomplete offset of ligand and protein desolvation due to poorly matched polar interactions. This analysis implies that, although Concanavalin A tolerates the additional 6 arm GlcNAc present in the pentasaccharide, it does not serve as a key recognition determinant.

| S-EPMC1301617 | biostudies-other

Molecular dynamics simulations to understand glycosaminoglycan interactions in the free- and protein-bound states.

Project description:Natural glycosaminoglycans (GAGs) are informational molecules with astounding structural diversity. Understanding the behavior of GAGs in the free and protein-bound states is critical for harnessing this diversity. Molecular dynamics (MD) offers atomistic insight into principles governing GAG recognition by proteins. Here, we discuss how MD can be used to understand local and global properties of GAGs in free solution, including torsions, puckering, hydrogen bonding, flexibility, and energetics. We discuss MD studies on GAG-protein complexes, which help elucidate the strength of interacting residues, role of water, energetics, and so on. The MD results accumulated so far suggest that GAG recognition of proteins is a continuum from the highly selective on one end to the fully non-selective on the other with intermediate levels of selectivity, including moderately selective and plastic. The advancements in MD technology, such as coarse-grained MD, coupled with really long simulations will help understand macroscale molecular movements in the future.

| S-EPMC9189024 | biostudies-literature

PyLipID: A Python Package for Analysis of Protein-Lipid Interactions from Molecular Dynamics Simulations.

Project description:Lipids play important modulatory and structural roles for membrane proteins. Molecular dynamics simulations are frequently used to provide insights into the nature of these protein-lipid interactions. Systematic comparative analysis requires tools that provide algorithms for objective assessment of such interactions. We introduce PyLipID, a Python package for the identification and characterization of specific lipid interactions and binding sites on membrane proteins from molecular dynamics simulations. PyLipID uses a community analysis approach for binding site detection, calculating lipid residence times for both the individual protein residues and the detected binding sites. To assist structural analysis, PyLipID produces representative bound lipid poses from simulation data, using a density-based scoring function. To estimate residue contacts robustly, PyLipID uses a dual-cutoff scheme to differentiate between lipid conformational rearrangements while bound from full dissociation events. In addition to the characterization of protein-lipid interactions, PyLipID is applicable to analysis of the interactions of membrane proteins with other ligands. By combining automated analysis, efficient algorithms, and open-source distribution, PyLipID facilitates the systematic analysis of lipid interactions from large simulation data sets of multiple species of membrane proteins.

| S-EPMC8830038 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data