Glycan synthesis, structure, and dynamics: A selection

Glycan structural information is a prerequisite for elucidation of carbohydrate function in biological systems. To this end we employ a tripod approach for investigation of carbohydrate 3D structure and dynamics based on organic synthesis; different experimental spectroscopy techniques, NMR being of prime importance; and molecular simulations using, in particular, molecular dynamics (MD) simulations. The synthesis of oligosaccharides in the form of glucosyl fluorides is described, and their use as substrates for the Lam16A E115S glucosyl synthase is exemplified as well as a conformational analysis of a cyclic β-(1→3)-heptaglucan based on molecular simulations. The flexibility of the N-acetyl group of aminosugars is by MD simulations indicated to function as a gatekeeper for transitions of glycosidic torsion angles to other regions of conformational space. A novel approach to visualize glycoprotein (GP) structures is presented in which the protein is shown by, for example, ribbons, but instead of stick or space-filling models for the carbohydrate portion it is visualized by the colored geometrical figures known as CFG representation in a 3D way, which we denote 3D-CFG, thereby effectively highlighting the sugar residues of the glycan part of the GP and the position(s) on the protein.

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EXPLORING THE PROTEIN LANDSCAPE IN RAMACHANDRAN SPACE: IT'S NOT JUST PSI-PHI

Journal of Bioinformatics and Computational Biology ◽

10.1142/s0219720009004400 ◽

2009 ◽

Vol 07 (06) ◽

pp. 1031-1037

Author(s):

WILLIAM KRIVAN ◽

DARRICK CARTER

Keyword(s):

Structural Information ◽

Three Dimensional ◽

Physical Space ◽

Rapid Screening ◽

Structural Comparison ◽

Torsion Angles ◽

Considerable Success ◽

Novel Approach ◽

Protein Shape

Most methods for the structural comparison of proteins utilize molecular coordinates in the three-dimensional physical space. Recently, a group has presented an elegant novel approach based on the characterization of protein shape in terms of backbone torsion angles. They have demonstrated considerable success in direct comparisons with other techniques, and their method lends itself to rapid screening of structural information from rapidly growing databases. We think that the torsion angle approach can be further strengthened by refining the distance notion that forms the basis of the computational scheme. In particular, we are suggesting to compute the distance along the path that minimizes the transition cost between aligned pairs of angles and therefore likely provides a more meaningful representation of distances between points in Ramachandran space.

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Oxidation state dependent conformational changes of HMGB1 regulates the formation of the CXCL12/HMGB1 heterocomplex

10.1101/555946 ◽

2019 ◽

Author(s):

Enrico M. A. Fassi ◽

Jacopo Sgrignani ◽

Gianluca D’Agostino ◽

Valentina Cecchinato ◽

Maura Garofalo ◽

...

Keyword(s):

Molecular Dynamics ◽

Disulfide Bond ◽

Conformational Changes ◽

Mammalian Cells ◽

Redox State ◽

High Mobility ◽

Md Simulations ◽

Conformational Space ◽

Structure And Dynamics ◽

State Dependent

AbstractHigh-mobility Group Box 1 (HMGB1) is an abundant protein present in all mammalian cells and involved in several processes. During inflammation or tissue damage, HMGB1 is released in the extracellular space and, depending on its redox state, can form a heterocomplex with CXCL12. The heterocomplex acts exclusively on the chemokine receptor CXCR4 enhancing leukocyte recruitment.Here, we used multi-microsecond molecular dynamics (MD) simulations to elucidate the effect of the disulfide bond on the structure and dynamics of HMGB1.The results of the MD simulations show that the presence or lack of the disulfide bond between Cys23 and Cys45 modulates the conformational space explored by HMGB1, making the reduced protein more suitable to form a complex with CXCL12.

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Conformational Isomerism of the Host as a Factor in Molecular Recognition in Host–Guest Inclusion Complexes: Example of Tris(5-acetyl-3-thienyl)methane

Acta Crystallographica Section B Structural Science ◽

10.1107/s0108768196010907 ◽

1997 ◽

Vol 53 (1) ◽

pp. 168-175 ◽

Cited By ~ 4

Author(s):

F. H. Herbstein

Keyword(s):

Inclusion Complex ◽

Inclusion Complexes ◽

Structural Information ◽

Boltzmann Distribution ◽

Carbonyl Oxygen ◽

Necessary Condition ◽

Structural Group ◽

Torsion Angles ◽

Different Types ◽

Acetyl Group

The tripod molecule tris(5-acetyl-3-thienyl)methane (TATM) is a flexile molecule, i.e. one that can occur in many conformationally isomeric states (conformers), which forms host–guest inclusion complexes with a large variety of guests (solvents). Some 40-odd different types of guest have been reported to form inclusion complexes. Five different types of crystal structure (all racemic), with nine different guests, have been reported in the literature and structural information is available for 17 crystallographically independent TATM molecules; most of the guests are disordered. Our analysis of this (substantial but, nevertheless, incomplete) database shows that each group of crystallographically isomorphous structures contains a particular TATM conformer with characteristic torsion angles about the bonds between methane carbon and the three thienyl rings (τ1, τ2 and τ3); the range of torsion angles in a particular structural group does not exceed 10°. Conformers are in addition distinguished via the stereochemistry of the acetyl group; there are approximately equal numbers of examples with carbonyl oxygen syn or anti to ring sulfur, intermediate conformations not being found. So far three different types of conformer have been encountered for the TATM molecule considered as an entity. A necessary condition for the occurrence of a particular conformer type is that the torsion angles τ1, τ2 and τ3 are such that ring H atoms should not approach more closely than (say) 2.4 Å, but this is not sufficient as considerably larger distances are found in some conformer types. Crystallization of the inclusion complex from a particular solvent can be envisaged to occur as follows. The TATM solution will contain a Boltzmann distribution of host conformers, the distribution depending on temperature but not on the nature of the solvent. Under suitable temperature and solubility conditions, the solvent will crystallize together with the appropriate conformer to form the inclusion complex-nuclei formed at this recognition stage, then grow into crystallites of the inclusion complex. The perturbed Boltzmann distribution (depleted in appropriate conformer) will continuously revert to its equilibrium form by conversion of the non-appropriate into the appropriate conformer as the crystallization proceeds.

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Split the Charge Difference in Two! a Rule of Thumb for Adding Proper Amounts of Ions in MD Simulations

10.26434/chemrxiv.9783155.v2 ◽

2020 ◽

Author(s):

Matías R. Machado ◽

Sergio Pantano

Keyword(s):

Molecular Dynamics ◽

Ionic Strength ◽

Molecular Simulations ◽

Md Simulations ◽

Good Practices ◽

Rule Of Thumb ◽

Ionic Concentrations

<p> Despite the relevance of properly setting ionic concentrations in Molecular Dynamics (MD) simulations, methods or practical rules to set ionic strength are scarce and rarely documented. Based on a recently proposed thermodynamics method we provide an accurate rule of thumb to define the electrolytic content in simulation boxes. Extending the use of good practices in setting up MD systems is promptly needed to ensure reproducibility and consistency in molecular simulations.</p>

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An Effective Cumulative Torsion Angles Model for Prediction of Protein Folding Rates

Protein and Peptide Letters ◽

10.2174/0929866526666191014152207 ◽

2020 ◽

Vol 27 (4) ◽

pp. 321-328 ◽

Cited By ~ 2

Author(s):

Yanru Li ◽

Ying Zhang ◽

Jun Lv

Keyword(s):

Protein Folding ◽

Size Structure ◽

Conformational Space ◽

Coefficient Of Determination ◽

Folding Rate ◽

Torsion Angles ◽

Folding Rates ◽

Protein Folding Rate ◽

Optimal Set ◽

Conformation Space

Background: Protein folding rate is mainly determined by the size of the conformational space to search, which in turn is dictated by factors such as size, structure and amino-acid sequence in a protein. It is important to integrate these factors effectively to form a more precisely description of conformation space. But there is no general paradigm to answer this question except some intuitions and empirical rules. Therefore, at the present stage, predictions of the folding rate can be improved through finding new factors, and some insights are given to the above question. Objective: Its purpose is to propose a new parameter that can describe the size of the conformational space to improve the prediction accuracy of protein folding rate. Method: Based on the optimal set of amino acids in a protein, an effective cumulative backbone torsion angles (CBTAeff) was proposed to describe the size of the conformational space. Linear regression model was used to predict protein folding rate with CBTAeff as a parameter. The degree of correlation was described by the coefficient of determination and the mean absolute error MAE between the predicted folding rates and experimental observations. Results: It achieved a high correlation (with the coefficient of determination of 0.70 and MAE of 1.88) between the logarithm of folding rates and the (CBTAeff)0.5 with experimental over 112 twoand multi-state folding proteins. Conclusion: The remarkable performance of our simplistic model demonstrates that CBTA based on optimal set was the major determinants of the conformation space of natural proteins.

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On the Use of the Discrete Constant pH Molecular Dynamics to Describe the Conformational Space of Peptides

Polymers ◽

10.3390/polym13010099 ◽

2020 ◽

Vol 13 (1) ◽

pp. 99

Author(s):

Cristian Privat ◽

Sergio Madurga ◽

Francesc Mas ◽

Jaime Rubio-Martínez

Keyword(s):

Molecular Dynamics ◽

Amino Acids ◽

Md Simulations ◽

Point Of View ◽

Conformational Space ◽

Conformational Sampling ◽

Protonation State ◽

Constant Ph ◽

Biochemical Systems ◽

Constant Ph Molecular Dynamics

Solvent pH is an important property that defines the protonation state of the amino acids and, therefore, modulates the interactions and the conformational space of the biochemical systems. Generally, this thermodynamic variable is poorly considered in Molecular Dynamics (MD) simulations. Fortunately, this lack has been overcome by means of the Constant pH Molecular Dynamics (CPHMD) methods in the recent decades. Several studies have reported promising results from these approaches that include pH in simulations but focus on the prediction of the effective pKa of the amino acids. In this work, we want to shed some light on the CPHMD method and its implementation in the AMBER suitcase from a conformational point of view. To achieve this goal, we performed CPHMD and conventional MD (CMD) simulations of six protonatable amino acids in a blocked tripeptide structure to compare the conformational sampling and energy distributions of both methods. The results reveal strengths and weaknesses of the CPHMD method in the implementation of AMBER18 version. The change of the protonation state according to the chemical environment is presumably an improvement in the accuracy of the simulations. However, the simulations of the deprotonated forms are not consistent, which is related to an inaccurate assignment of the partial charges of the backbone atoms in the CPHMD residues. Therefore, we recommend the CPHMD methods of AMBER program but pointing out the need to compare structural properties with experimental data to bring reliability to the conformational sampling of the simulations.

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Predicting the Structure and Dynamics of Membrane Protein GerAB from Bacillus subtilis

International Journal of Molecular Sciences ◽

10.3390/ijms22073793 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3793

Author(s):

Sophie Blinker ◽

Jocelyne Vreede ◽

Peter Setlow ◽

Stanley Brul

Keyword(s):

Bacillus Subtilis ◽

Membrane Protein ◽

Spore Germination ◽

Structural Information ◽

Transmembrane Protein ◽

Homology Modelling ◽

Water Channel ◽

Md Simulations ◽

Integral Membrane Protein ◽

Starting Point

Bacillus subtilis forms dormant spores upon nutrient depletion. Germinant receptors (GRs) in spore’s inner membrane respond to ligands such as L-alanine, and trigger spore germination. In B. subtilis spores, GerA is the major GR, and has three subunits, GerAA, GerAB, and GerAC. L-Alanine activation of GerA requires all three subunits, but which binds L-alanine is unknown. To date, how GRs trigger germination is unknown, in particular due to lack of detailed structural information about B subunits. Using homology modelling with molecular dynamics (MD) simulations, we present structural predictions for the integral membrane protein GerAB. These predictions indicate that GerAB is an α-helical transmembrane protein containing a water channel. The MD simulations with free L-alanine show that alanine binds transiently to specific sites on GerAB. These results provide a starting point for unraveling the mechanism of L-alanine mediated signaling by GerAB, which may facilitate early events in spore germination.

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Conformational Ensembles by NMR and MD Simulations in Model Heptapeptides with Select Tri-Peptide Motifs

International Journal of Molecular Sciences ◽

10.3390/ijms22031364 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1364

Author(s):

V. V. Krishnan ◽

Timothy Bentley ◽

Alina Xiong ◽

Kalyani Maitra

Keyword(s):

Principal Component ◽

Md Simulations ◽

Conformational Space ◽

Random Coil ◽

Radius Of Gyration ◽

Small Peptides ◽

Conformational Ensembles ◽

Solution State ◽

Peptide Motifs ◽

Explicit Solvent

Both nuclear magnetic resonance (NMR) and molecular dynamics (MD) simulations are routinely used in understanding the conformational space sampled by peptides in the solution state. To investigate the role of single-residue change in the ensemble of conformations sampled by a set of heptapeptides, AEVXEVG with X = L, F, A, or G, comprehensive NMR, and MD simulations were performed. The rationale for selecting the particular model peptides is based on the high variability in the occurrence of tri-peptide E*L between the transmembrane β-barrel (TMB) than in globular proteins. The ensemble of conformations sampled by E*L was compared between the three sets of ensembles derived from NMR spectroscopy, MD simulations with explicit solvent, and the random coil conformations. In addition to the estimation of global determinants such as the radius of gyration of a large sample of structures, the ensembles were analyzed using principal component analysis (PCA). In general, the results suggest that the -EVL- peptide indeed adopts a conformational preference that is distinctly different not only from a random distribution but also from other peptides studied here. The relatively straightforward approach presented herein could help understand the conformational preferences of small peptides in the solution state.

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TomoSAR Mapping of 3D Forest Structure: Contributions of L-Band Configurations

Remote Sensing ◽

10.3390/rs13122255 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2255

Author(s):

Matteo Pardini ◽

Victor Cazcarra-Bes ◽

Konstantinos Papathanassiou

Keyword(s):

Information Content ◽

Forest Structure ◽

Structural Information ◽

3D Structure ◽

Physical Structure ◽

Structure Mapping ◽

Structure Information ◽

Forest Sites ◽

L Band ◽

Structure Indices

Synthetic Aperture Radar (SAR) measurements are unique for mapping forest 3D structure and its changes in time. Tomographic SAR (TomoSAR) configurations exploit this potential by reconstructing the 3D radar reflectivity. The frequency of the SAR measurements is one of the main parameters determining the information content of the reconstructed reflectivity in terms of penetration and sensitivity to the individual vegetation elements. This paper attempts to review and characterize the structural information content of L-band TomoSAR reflectivity reconstructions, and their potential to forest structure mapping. First, the challenges in the accurate TomoSAR reflectivity reconstruction of volume scatterers (which are expected to dominate at L-band) and to extract physical structure information from the reconstructed reflectivity is addressed. Then, the L-band penetration capability is directly evaluated by means of the estimation performance of the sub-canopy ground topography. The information content of the reconstructed reflectivity is then evaluated in terms of complementary structure indices. Finally, the dependency of the TomoSAR reconstruction and of its structural information to both the TomoSAR acquisition geometry and the temporal change of the reflectivity that may occur in the time between the TomoSAR measurements in repeat-pass or bistatic configurations is evaluated. The analysis is supported by experimental results obtained by processing airborne acquisitions performed over temperate forest sites close to the city of Traunstein in the south of Germany.

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NMR-Based Structural Characterization of a Two-Disulfide-Bonded Analogue of the FXIIIa Inhibitor Tridegin: New Insights into Structure–Activity Relationships

International Journal of Molecular Sciences ◽

10.3390/ijms22020880 ◽

2021 ◽

Vol 22 (2) ◽

pp. 880

Author(s):

Thomas Schmitz ◽

Ajay Abisheck Paul George ◽

Britta Nubbemeyer ◽

Charlotte A. Bäuml ◽

Torsten Steinmetzer ◽

...

Keyword(s):

Structural Information ◽

Coagulation Factor ◽

Md Simulations ◽

2D Nmr ◽

Label Free ◽

2D Nmr Spectroscopy ◽

Structure Information ◽

Structure Activity Relationships ◽

Structure Activity ◽

Blood Sucking

The saliva of blood-sucking leeches contains a plethora of anticoagulant substances. One of these compounds derived from Haementeria ghilianii, the 66mer three-disulfide-bonded peptide tridegin, specifically inhibits the blood coagulation factor FXIIIa. Tridegin represents a potential tool for antithrombotic and thrombolytic therapy. We recently synthesized two-disulfide-bonded tridegin variants, which retained their inhibitory potential. For further lead optimization, however, structure information is required. We thus analyzed the structure of a two-disulfide-bonded tridegin isomer by solution 2D NMR spectroscopy in a combinatory approach with subsequent MD simulations. The isomer was studied using two fragments, i.e., the disulfide-bonded N-terminal (Lys1–Cys37) and the flexible C-terminal part (Arg38–Glu66), which allowed for a simplified, label-free NMR-structure elucidation of the 66mer peptide. The structural information was subsequently used in molecular modeling and docking studies to provide insights into the structure–activity relationships. The present study will prospectively support the development of anticoagulant-therapy-relevant compounds targeting FXIIIa.

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