Stochastic conformational search on the Lewis X (Lex) trisaccharide and three Lex analogues

2002 ◽  
Vol 80 (8) ◽  
pp. 1088-1095 ◽  
Author(s):  
France-Isabelle Auzanneau ◽  
Elizabeth Sourial ◽  
Jonathan M Schmidt ◽  
Miklos Feher
Keyword(s):  
Molecular Modeling ◽  
Three Dimensional ◽  
Cross Reactivity ◽  
Stochastic Search ◽  
Conformational Search ◽  
Sugar Residue ◽  
Lewis X ◽  
X Ray Crystallography ◽  
Cancerous Cells ◽  
Fucose Residue

Biased stochastic conformational searches using the MMFF94 force field and the Born continuum solvation model were applied to the molecular modeling of the Lewis X (Lex) trisaccharide (β-D-Gal-(1,4)-[α-L-Fuc-(1,3)]-β-D-GlcNAc-OH) and three Lex analogues, in which each of the three sugar units was replaced by another sugar residue, i.e., N-acetyl-glucosamine by glucose, galactose by glucose, and fucose by rhamnose. The stochastic search accurately identified a lowest energy conformation of the Lex determinant that corresponds to the reported conformations of Lex deduced experimentally in the solid state by X-ray crystallography and in solution by NMR measurements. In this conformation stacking exists between the galactosyl and fucosyl residues. Five new local minima for the Lex trisaccharide were found within 3 kcal mol–1 of the global minimum using the stochastic search and metric scaling. Modeling studies of the analogues showed that the stacking observed in the Lex trisaccharide was maintained when either galactosyl or N-acetylglucosamine were replaced by glucosyl residues. In contrast, substitution of the fucose residue by rhamnose led to two conformers in which stacking of the galactose and rhamnose residues was no longer maintained. These results indicate that the substitution of the non-reducing end galactosyl or N-acetyl-glucosaminyl residues by a glucose unit in the dimeric Lewis X (dimLex) tumour associated antigen could help in the development of a vaccine that cross-reacts with dimLex but no longer displays Lex associated three-dimensional epitopes also presented by non-cancerous cells. In contrast, an analogue in which the fucosyl residue is replaced by rhamnose does not constitute a good vaccine candidate, since our results indicate that this substitution will induce an important conformational change that is likely to abolish cross-reactivity with the natural dimLex tumor associated antigen.Key words: molecular modeling, stochastic, conformational analysis, Lewis X, oligosaccharide.

scholarly journals Induction of Rare Conformation of Oligosaccharide by Binding to Calcium-dependent Bacterial Lectin: X-ray Crystallography and Modelling Study

2019 ◽  
Author(s):  
Martin Lepsik ◽  
Roman Sommer ◽  
Sakonwan Kuhaudomlarp ◽  
Mickaёl Lelimousin ◽  
Emanuele Paci ◽  
...  
Keyword(s):  
Force Field ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Lewis X ◽  
X Ray ◽  
X Ray Crystallography ◽  
Calcium Dependent ◽  
Protein Receptors ◽  
Dependent Protein ◽  
Micro Organisms

ABSTRACTPathogenic micro-organisms utilize protein receptors in adhesion to host tissues, a process that in some cases relies on the interaction between lectin and human glycoconjugates. Oligosaccharide epitopes are recognized through their three-dimensional structure and their flexibility is a key issue in specificity. In this paper, we analyse by X-ray crystallography the structures of the lectin LecB from two strains of Pseudomonas aeruginosa in complex with Lewis x oligosaccharide present on cell surfaces of human tissues. An unusual conformation of the glycan was observed in all binding sites with a non-canonical syn orientation of the N-acetyl group of N-acetyl-glucosamine. A PDB-wide search revealed that such an orientation occurs only in 2% of protein/carbohydrate complexes. Theoretical chemistry calculations showed that the observed conformation is unstable in solution but stabilised by the lectin. A reliable description of LecB/Lewis x complex by force field-based methods had proven as especially challenging due to the special feature of the binding site, two closely apposed Ca2+ ions which induce strong charge delocalisation. By comparing various force-field parametrisations, we design general protocols which will be useful in near future for designing carbohydrate-based ligands (glycodrugs) against other calcium-dependent protein receptors.

3-D reconstruction of molecular shape from microcrystal thin sections

1983 ◽  
Vol 41 ◽  
pp. 748-749
Author(s):  
S. Cusack ◽  
J.-C. Jésior
Keyword(s):  
Three Dimensional ◽  
Molecular Shape ◽  
Biological Molecules ◽  
Fourier Space ◽  
Single Particles ◽  
Thin Sections ◽  
Standard Methods ◽  
X Ray ◽  
X Ray Crystallography ◽  
Dimensional Reconstruction

Three-dimensional reconstruction techniques using electron microscopy have been principally developed for application to 2-D arrays (i.e. monolayers) of biological molecules and symmetrical single particles (e.g. helical viruses). However many biological molecules that crystallise form multilayered microcrystals which are unsuitable for study by either the standard methods of 3-D reconstruction or, because of their size, by X-ray crystallography. The grid sectioning technique enables a number of different projections of such microcrystals to be obtained in well defined directions (e.g. parallel to crystal axes) and poses the problem of how best these projections can be used to reconstruct the packing and shape of the molecules forming the microcrystal.Given sufficient projections there may be enough information to do a crystallographic reconstruction in Fourier space. We however have considered the situation where only a limited number of projections are available, as for example in the case of catalase platelets where three orthogonal and two diagonal projections have been obtained (Fig. 1).

Modulation of Toll-Like Receptor 4. Insights from X-Ray Crystallography and Molecular Modeling

2015 ◽  
Vol 14 (23) ◽  
pp. 2672-2683 ◽  
Author(s):  
Javier Klett ◽  
Jake Reeves ◽  
Nils Oberhauser ◽  
Lucia Perez-Regidor ◽  
Sonsoles Martin-Santamaria
Keyword(s):  
Molecular Modeling ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
X Ray ◽  
X Ray Crystallography

scholarly journals Weak Interactions in Cocrystals of Isoniazid with Glycolic and Mandelic Acids

Crystals ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 328
Author(s):  
Raquel Álvarez-Vidaurre ◽  
Alfonso Castiñeiras ◽  
Antonio Frontera ◽  
Isabel García-Santos ◽  
Diego M. Gil ◽  
...  
Keyword(s):  
Density Functional ◽  
Glycolic Acid ◽  
Weak Interactions ◽  
Three Dimensional ◽  
Functional Theory ◽  
Molecular Systems ◽  
X Ray Crystallography ◽  
Hydroxycarboxylic Acids ◽  
Non Covalent Interactions ◽  
Covalent Interactions

This work deals with the preparation of pyridine-3-carbohydrazide (isoniazid, inh) cocrystals with two α-hydroxycarboxylic acids. The interaction of glycolic acid (H2ga) or d,l-mandelic acid (H2ma) resulted in the formation of cocrystals or salts of composition (inh)·(H2ga) (1) and [Hinh]+[Hma]–·(H2ma) (2) when reacted with isoniazid. An N′-(propan-2-ylidene)isonicotinic hydrazide hemihydrate, (pinh)·1/2(H2O) (3), was also prepared by condensation of isoniazid with acetone in the presence of glycolic acid. These prepared compounds were well characterized by elemental analysis, and spectroscopic methods, and their three-dimensional molecular structure was determined by single crystal X-ray crystallography. Hydrogen bonds involving the carboxylic acid occur consistently with the pyridine ring N atom of the isoniazid and its derivatives. The remaining hydrogen-bonding sites on the isoniazid backbone vary based on the steric influences of the derivative group. These are contrasted in each of the molecular systems. Finally, Hirshfeld surface analysis and Density-functional theory (DFT) calculations (including NCIplot and QTAIM analyses) have been performed to further characterize and rationalize the non-covalent interactions.

scholarly journals Structure Solution of Nano-Crystalline Small Molecules Using MicroED and Solid-State NMR Dipolar-Based Experiments

Molecules ◽  
2021 ◽  
Vol 26 (15) ◽  
pp. 4652
Author(s):  
Nghia Tuan Duong ◽  
Yoshitaka Aoyama ◽  
Katsumi Kawamoto ◽  
Toshio Yamazaki ◽  
Yusuke Nishiyama
Keyword(s):  
Spin Dynamics ◽  
Double Resonance ◽  
Three Dimensional ◽  
Saturation Pulse ◽  
X Ray Crystallography ◽  
Nano Crystalline ◽  
Structure Solution ◽  
Validation Procedure ◽  
R Factors ◽  
Shift Calculation

Three-dimensional electron diffraction crystallography (microED) can solve structures of sub-micrometer crystals, which are too small for single crystal X-ray crystallography. However, R factors for the microED-based structures are generally high because of dynamic scattering. That means R factor may not be reliable provided that kinetic analysis is used. Consequently, there remains ambiguity to locate hydrogens and to assign nuclei with close atomic numbers, like carbon, nitrogen, and oxygen. Herein, we employed microED and ssNMR dipolar-based experiments together with spin dynamics numerical simulations. The NMR dipolar-based experiments were 1H-14N phase-modulated rotational-echo saturation-pulse double-resonance (PM-S-RESPDOR) and 1H-1H selective recoupling of proton (SERP) experiments. The former examined the dephasing effect of a specific 1H resonance under multiple 1H-14N dipolar couplings. The latter examined the selective polarization transfer between a 1H-1H pair. The structure was solved by microED and then validated by evaluating the agreement between experimental and calculated dipolar-based NMR results. As the measurements were performed on 1H and 14N, the method can be employed for natural abundance samples. Furthermore, the whole validation procedure was conducted at 293 K unlike widely used chemical shift calculation at 0 K using the GIPAW method. This combined method was demonstrated on monoclinic l-histidine.

scholarly journals Three-Dimensional Structures of Carbohydrates and Where to Find Them

2020 ◽  
Vol 21 (20) ◽  
pp. 7702 ◽  
Author(s):  
Sofya I. Scherbinina ◽  
Philip V. Toukach
Keyword(s):  
Experimental Data ◽  
Molecular Modeling ◽  
Computational Methods ◽  
Three Dimensional ◽  
Structural Diversity ◽  
Structural Data ◽  
Structural Features ◽  
Data Validation ◽  
Data Generation ◽  
Efficient Treatment

Analysis and systematization of accumulated data on carbohydrate structural diversity is a subject of great interest for structural glycobiology. Despite being a challenging task, development of computational methods for efficient treatment and management of spatial (3D) structural features of carbohydrates breaks new ground in modern glycoscience. This review is dedicated to approaches of chemo- and glyco-informatics towards 3D structural data generation, deposition and processing in regard to carbohydrates and their derivatives. Databases, molecular modeling and experimental data validation services, and structure visualization facilities developed for last five years are reviewed.

Three-dimensional crystallization of membrane proteins

1988 ◽  
Vol 21 (4) ◽  
pp. 429-477 ◽  
Author(s):  
W. Kühlbrandt
Keyword(s):  
High Resolution ◽  
Membrane Proteins ◽  
Membrane Protein ◽  
Protein Complexes ◽  
Three Dimensional ◽  
Biological Macromolecules ◽  
X Ray ◽  
X Ray Crystallography ◽  
Membrane Protein Complexes ◽  
Essential Prerequisite

As recently as 10 years ago, the prospect of solving the structure of any membrane protein by X-ray crystallography seemed remote. Since then, the threedimensional (3-D) structures of two membrane protein complexes, the bacterial photosynthetic reaction centres of Rhodopseudomonas viridis (Deisenhofer et al. 1984, 1985) and of Rhodobacter sphaeroides (Allen et al. 1986, 1987 a, 6; Chang et al. 1986) have been determined at high resolution. This astonishing progress would not have been possible without the pioneering work of Michel and Garavito who first succeeded in growing 3-D crystals of the membrane proteins bacteriorhodopsin (Michel & Oesterhelt, 1980) and matrix porin (Garavito & Rosenbusch, 1980). X-ray crystallography is still the only routine method for determining the 3-D structures of biological macromolecules at high resolution and well-ordered 3-D crystals of sufficient size are the essential prerequisite.

Crystal structure of the hinge domain of Smchd1 reveals its dimerization mode and nucleic acid–binding residues

2020 ◽  
Vol 13 (636) ◽  
pp. eaaz5599 ◽  
Author(s):  
Kelan Chen ◽  
Richard W. Birkinshaw ◽  
Alexandra D. Gurzau ◽  
Iromi Wanigasuriya ◽  
Ruoyun Wang ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Muscular Dystrophy ◽  
Three Dimensional ◽  
Underlying Mechanism ◽  
Structural Features ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Dimensional Structure ◽  
Nucleic Acid Binding ◽  
X Ray Crystallography ◽  
Hinge Domain

Structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) is an epigenetic regulator in which polymorphisms cause the human developmental disorder, Bosma arhinia micropthalmia syndrome, and the degenerative disease, facioscapulohumeral muscular dystrophy. SMCHD1 is considered a noncanonical SMC family member because its hinge domain is C-terminal, because it homodimerizes rather than heterodimerizes, and because SMCHD1 contains a GHKL-type, rather than an ABC-type ATPase domain at its N terminus. The hinge domain has been previously implicated in chromatin association; however, the underlying mechanism involved and the basis for SMCHD1 homodimerization are unclear. Here, we used x-ray crystallography to solve the three-dimensional structure of the Smchd1 hinge domain. Together with structure-guided mutagenesis, we defined structural features of the hinge domain that participated in homodimerization and nucleic acid binding, and we identified a functional hotspot required for chromatin localization in cells. This structure provides a template for interpreting the mechanism by which patient polymorphisms within the SMCHD1 hinge domain could compromise function and lead to facioscapulohumeral muscular dystrophy.

scholarly journals Fast, Efficient Fragment-Based Coordinate Generation for Open Babel

2019 ◽  
Author(s):  
Naruki Yoshikawa ◽  
Geoffrey Hutchison
Keyword(s):  
Molecular Modeling ◽  
Structure Prediction ◽  
Distance Geometry ◽  
Three Dimensional ◽  
Property Prediction ◽  
Crystallographic Databases ◽  
Fragment Library ◽  
Wide Range ◽  
Computational Property ◽  
Improving Accuracy

<div>Rapidly predicting an accurate three dimensional geometry of a molecule is a crucial task in cheminformatics and a range of molecular modeling. Fast, accurate, and open implementation of structure prediction is necessary for reproducible cheminformatics research. We introduce fragment-based coordinate generation for Open Babel, a widely accepted open source toolkit for cheminformatics. The new implementation significant improves speed and stereochemical accuracy, while retaining or improving accuracy of bond lengths, bond angles, and dihedral torsions. We first separate an input molecule into fragments by cutting at rotatable bonds. Coordinates of fragments are set according to the fragment library, which is prepared from open crystallographic databases. Since coordinates of multiple atoms are decided at once, coordinate prediction is accelerated over the previous rules-based implementation or the widely-used distance geometry methods in RDKit. This new implementation will be beneficial for a wide range of applications, including computational property prediction in polymers, molecular materials and drug design.</div>

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