scholarly journals Stabilization of the Hinge Region of Human E-selectin Enhances Binding Affinity to Ligands Under Force

2021 ◽  
Vol 14 (1) ◽  
pp. 65-74
Author(s):  
Thong M. Cao ◽  
Michael R. King
Keyword(s):  
Molecular Dynamics ◽  
Cell Adhesion ◽  
Tensile Force ◽  
Md Simulations ◽  
Single Amino Acid ◽  
Lectin Domain ◽  
Cell Rolling ◽  
Extended Conformation ◽  
Sialyl Lewis ◽  
Selectin Family

Abstract Introduction E-selectin is a member of the selectin family of cell adhesion molecules expressed on the plasma membrane of inflamed endothelium and facilitates initial leukocyte tethering and subsequent cell rolling during the early stages of the inflammatory response via binding to glycoproteins expressing sialyl LewisX and sialyl LewisA (sLeX/A). Existing crystal structures of the extracellular lectin/EGF-like domain of E-selectin complexed with sLeX have revealed that E-selectin can exist in two conformation states, a low affinity (bent) conformation, and a high affinity (extended) conformation. The differentiating characteristic of the two conformations is the interdomain angle between the lectin and the EGF-like domain. Methods Using molecular dynamics (MD) simulations we observed that in the absence of tensile force E-selectin undergoes spontaneous switching between the two conformational states at equilibrium. A single amino acid substitution at residue 2 (serine to tyrosine) on the lectin domain favors the extended conformation. Results Steered molecular dynamics (SMD) simulations of E-selectin and PSGL-1 in conjunction with experimental cell adhesion assays show a longer binding lifetime of E-selectin (S2Y) to PSGL-1 compared to wildtype protein. Conclusions The findings in this study advance our understanding into how the structural makeup of E-selectin allosterically influences its adhesive dynamics.

scholarly journals Identification of rare Lewis oligosaccharide conformers in aqueous solution using enhanced sampling molecular dynamics

2017 ◽  
Author(s):  
Irfan Alibay ◽  
Kepa K. Burusco ◽  
Neil J. Bruce ◽  
Richard A. Bryce
Keyword(s):  
Molecular Dynamics ◽  
Aqueous Solution ◽  
Md Simulations ◽  
Umbrella Sampling ◽  
Biological Action ◽  
Sialyl Lewis X ◽  
Enhanced Sampling ◽  
Sialyl Lewis ◽  
Aqueous Solvent ◽  
A Minor

<p>Determining the conformations accessible to carbohydrate ligands in aqueous solution is important for understanding their biological action. In this work, we evaluate the conformational free energy surfaces of Lewis oligosaccharides in explicit aqueous solvent using a multidimensional variant of the swarm-enhanced sampling molecular dynamics (msesMD) method; we compare with multi-microsecond unbiased MD simulations, umbrella sampling and accelerated MD approaches. For the sialyl Lewis A tetrasaccharide, msesMD simulations in aqueous solution predict conformer landscapes in general agreement with the other biased methods and with triplicate unbiased 10 ms trajectories; these simulations find a predominance of closed conformer and a range of low occupancy open forms. The msesMD simulations also suggest closed-to-open transitions in the tetrasaccharide are facilitated by changes in ring puckering of its GlcNAc residue away from the <sup>4</sup>C<sub>1</sub> form, in line with previous work. For sialyl Lewis X tetrasaccharide, msesMD simulations predict a minor population of an open form in solution, corresponding to a rare lectin-bound pose observed crystallographically. Overall, from comparison with biased MD calculations, we find that triplicate 10 ms unbiased MD simulations may not be enough to fully sample glycan conformations in aqueous solution. However, the computational efficiency and intuitive approach of the msesMD method suggest potential for its application in glycomics as a tool for analysis of oligosaccharide conformation.</p>

scholarly journals Molecular dynamics simulations for genetic interpretation in protein coding regions: where we are, where to go and when

2019 ◽  
Author(s):  
Juan J Galano-Frutos ◽  
Helena García-Cebollada ◽  
Javier Sancho
Keyword(s):  
Molecular Dynamics ◽  
Amino Acid ◽  
Large Scale ◽  
Binary Classification ◽  
Chemical Properties ◽  
Md Simulations ◽  
Single Amino Acid ◽  
Medical Decision ◽  
Evolutionary Information ◽  
Protein Variants

Abstract The increasing ease with which massive genetic information can be obtained from patients or healthy individuals has stimulated the development of interpretive bioinformatics tools as aids in clinical practice. Most such tools analyze evolutionary information and simple physical–chemical properties to predict whether replacement of one amino acid residue with another will be tolerated or cause disease. Those approaches achieve up to 80–85% accuracy as binary classifiers (neutral/pathogenic). As such accuracy is insufficient for medical decision to be based on, and it does not appear to be increasing, more precise methods, such as full-atom molecular dynamics (MD) simulations in explicit solvent, are also discussed. Then, to describe the goal of interpreting human genetic variations at large scale through MD simulations, we restrictively refer to all possible protein variants carrying single-amino-acid substitutions arising from single-nucleotide variations as the human variome. We calculate its size and develop a simple model that allows calculating the simulation time needed to have a 0.99 probability of observing unfolding events of any unstable variant. The knowledge of that time enables performing a binary classification of the variants (stable-potentially neutral/unstable-pathogenic). Our model indicates that the human variome cannot be simulated with present computing capabilities. However, if they continue to increase as per Moore’s law, it could be simulated (at 65°C) spending only 3 years in the task if we started in 2031. The simulation of individual protein variomes is achievable in short times starting at present. International coordination seems appropriate to embark upon massive MD simulations of protein variants.

scholarly journals Mechanical Model for Catch-Bond-Mediated Cell Adhesion in Shear Flow

2020 ◽  
Vol 21 (2) ◽  
pp. 584 ◽  
Author(s):  
Long Li ◽  
Wei Kang ◽  
Jizeng Wang
Keyword(s):  
Cell Adhesion ◽  
Shear Rate ◽  
Shear Flow ◽  
Mechanical Model ◽  
Tensile Force ◽  
Current View ◽  
Analytical Mechanics ◽  
Catch Bond ◽  
Cell Rolling ◽  
Theoretical Predictions

Catch bond, whose lifetime increases with applied tensile force, can often mediate rolling adhesion of cells in a hydrodynamic environment. However, the mechanical mechanism governing the kinetics of rolling adhesion of cells through catch-bond under shear flow is not yet clear. In this study, a mechanical model is proposed for catch-bond-mediated cell adhesion in shear flow. The stochastic reaction of bond formation and dissociation is described as a Markovian process, whereas the dynamic motion of cells follows classical analytical mechanics. The steady state of cells significantly depends on the shear rate of flow. The upper and lower critical shear rates required for cell detachment and attachment are extracted, respectively. When the shear rate increases from the lower threshold to the upper threshold, cell rolling became slower and more regular, implying the flow-enhanced adhesion phenomenon. Our results suggest that this flow-enhanced stability of rolling adhesion is attributed to the competition between stochastic reactions of bonds and dynamics of cell rolling, instead of force lengthening the lifetime of catch bonds, thereby challenging the current view in understanding the mechanism behind this flow-enhanced adhesion phenomenon. Moreover, the loading history of flow defining bistability of cell adhesion in shear flow is predicted. These theoretical predictions are verified by Monte Carlo simulations and are related to the experimental observations reported in literature.

scholarly journals P- and E-selectin use common sites for carbohydrate ligand recognition and cell adhesion.

1993 ◽  
Vol 120 (5) ◽  
pp. 1227-1235 ◽  
Author(s):  
D V Erbe ◽  
S R Watson ◽  
L G Presta ◽  
B A Wolitzky ◽  
C Foxall ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Sialic Acid ◽  
Sialyl Lewis X ◽  
Homologous Region ◽  
Carbohydrate Recognition ◽  
Lectin Domain ◽  
Calcium Dependent ◽  
Sialyl Lewis ◽  
Adhesive Interactions ◽  
Carbohydrate Ligand

The selectins are a family of three calcium-dependent lectins that mediate adhesive interactions between leukocytes and the endothelium during normal and abnormal inflammatory episodes. Previous work has implicated the carbohydrate sialyl Lewis(x) (sLe(x); sialic acid alpha 2-3 galactose beta 1-4 [Fucose alpha 1-3] N-acetyl glucosamine) as a component of the ligand recognized by E- and P-selectin. In the case of P-selectin, other components of the cell surface, including 2'6-linked sialic acid and sulfatide (galactose-4-sulfate ceramide), have also been proposed for adhesion mediated by this selectin. We have recently defined a region of the E-selectin lectin domain that appears to be directly involved with carbohydrate recognition and cell adhesion (Erbe, D. V., B. A. Wolitzky, L. G. Presta, C. R. Norton, R. J. Ramos, D. K. Burns, R. M. Rumberger, B. N. N. Rao, C. Foxall, B. K. Brandley, and L. A. Lasky. 1992. J. Cell Biol. 119:215-227). Here we describe a similar analysis of the P-selectin lectin domain which demonstrates that a homologous region of this glycoprotein's lectin motif is involved with carbohydrate recognition and cell binding. In addition, we present evidence that is inconsistent with a biological role for either 2'6-linked sialic acid or sulfatide in P-selectin-mediated adhesion. These results suggest that a common region of the E- and P-selectin lectin domains appears to mediate carbohydrate recognition and cell adhesion.

scholarly journals Identification of rare Lewis oligosaccharide conformers in aqueous solution using enhanced sampling molecular dynamics

2017 ◽  
Author(s):  
Irfan Alibay ◽  
Kepa K. Burusco ◽  
Neil J. Bruce ◽  
Richard A. Bryce
Keyword(s):  
Molecular Dynamics ◽  
Aqueous Solution ◽  
Md Simulations ◽  
Umbrella Sampling ◽  
Biological Action ◽  
Sialyl Lewis X ◽  
Enhanced Sampling ◽  
Sialyl Lewis ◽  
Aqueous Solvent ◽  
A Minor

<p>Determining the conformations accessible to carbohydrate ligands in aqueous solution is important for understanding their biological action. In this work, we evaluate the conformational free energy surfaces of Lewis oligosaccharides in explicit aqueous solvent using a multidimensional variant of the swarm-enhanced sampling molecular dynamics (msesMD) method; we compare with multi-microsecond unbiased MD simulations, umbrella sampling and accelerated MD approaches. For the sialyl Lewis A tetrasaccharide, msesMD simulations in aqueous solution predict conformer landscapes in general agreement with the other biased methods and with triplicate unbiased 10 ms trajectories; these simulations find a predominance of closed conformer and a range of low occupancy open forms. The msesMD simulations also suggest closed-to-open transitions in the tetrasaccharide are facilitated by changes in ring puckering of its GlcNAc residue away from the <sup>4</sup>C<sub>1</sub> form, in line with previous work. For sialyl Lewis X tetrasaccharide, msesMD simulations predict a minor population of an open form in solution, corresponding to a rare lectin-bound pose observed crystallographically. Overall, from comparison with biased MD calculations, we find that triplicate 10 ms unbiased MD simulations may not be enough to fully sample glycan conformations in aqueous solution. However, the computational efficiency and intuitive approach of the msesMD method suggest potential for its application in glycomics as a tool for analysis of oligosaccharide conformation.</p>

Molecular dynamics simulations of gallium nitride nanosheets under uniaxial and biaxial tensile loads

2018 ◽  
Vol 32 (05) ◽  
pp. 1850051
Author(s):  
Saeed Rouhi ◽  
Hamoon Pourmirzaagha ◽  
Mostafa Omidi Bidgoli
Keyword(s):  
Molecular Dynamics ◽  
Gallium Nitride ◽  
Biaxial Loading ◽  
Tensile Force ◽  
Fracture Initiation ◽  
Md Simulations ◽  
Width Ratio ◽  
Biaxial Tensile ◽  
Different Strains ◽  
Dynamics Simulations

Molecular dynamics (MD) simulations are employed to study the elastic properties of gallium nitride (GaN) nanosheets. Young’s and bulk moduli of GaN nanosheets with different side lengths and height/width ratio are obtained. Besides, the configuration of the nanosheet at different strains is represented until the fracture initiation and final fracture are observed. It is seen that the zigzag nanosheets have larger elastic moduli than armchair ones with the same sizes. Moreover, increasing the length size of the nanosheets results in decreasing Young’s modulus. Bulk moduli of GaN nanosheets are also obtained by applying biaxial loading on all edges. It is seen that under the biaxial tensile force, the fracture is initiated at the nanosheet corners and is continued toward the nanosheet center. A nonlinear relation between the bulk modulus and nanosheet size is observed.

Efficient Treatment of Fixed and Induced Dipolar Interactions

2000 ◽  
Vol 653 ◽  
Author(s):  
Celeste Sagui ◽  
Thoma Darden
Keyword(s):  
Molecular Dynamics ◽  
Md Simulations ◽  
Lagrangian Formalism ◽  
Dipolar Interactions ◽  
Time Step ◽  
Efficient Treatment ◽  
Particle Mesh Ewald ◽  
Fixed Charges ◽  
Self Consistency ◽  
Induced Dipoles

AbstractFixed and induced point dipoles have been implemented in the Ewald and Particle-Mesh Ewald (PME) formalisms. During molecular dynamics (MD) the induced dipoles can be propagated along with the atomic positions either by interation to self-consistency at each time step, or by a Car-Parrinello (CP) technique using an extended Lagrangian formalism. The use of PME for electrostatics of fixed charges and induced dipoles together with a CP treatment of dipole propagation in MD simulations leads to a cost overhead of only 33% above that of MD simulations using standard PME with fixed charges, allowing the study of polarizability in largemacromolecular systems.

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

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>

Assessing the Antimalarial Potentials of Phytochemicals: Virtual Screening, Molecular Dynamics and In-Vitro Investigations

2019 ◽  
Vol 16 (3) ◽  
pp. 291-300
Author(s):  
Saumya K. Patel ◽  
Mohd Athar ◽  
Prakash C. Jha ◽  
Vijay M. Khedkar ◽  
Yogesh Jasrai ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Structural Integrity ◽  
Md Simulations ◽  
Tylophora Indica ◽  
Multidrug Resistance Protein 1 ◽  
Receptor Complexes ◽  
Resistance Protein ◽  
Dynamics Simulations ◽  
Stable Trajectory

Background: Combined in-silico and in-vitro approaches were adopted to investigate the antiplasmodial activity of Catharanthus roseus and Tylophora indica plant extracts as well as their isolated components (vinblastine, vincristine and tylophorine). </P><P> Methods: We employed molecular docking to prioritize phytochemicals from a library of 26 compounds against Plasmodium falciparum multidrug-resistance protein 1 (PfMDR1). Furthermore, Molecular Dynamics (MD) simulations were performed for a duration of 10 ns to estimate the dynamical structural integrity of ligand-receptor complexes. </P><P> Results: The retrieved bioactive compounds viz. tylophorine, vinblastin and vincristine were found to exhibit significant interacting behaviour; as validated by in-vitro studies on chloroquine sensitive (3D7) as well as chloroquine resistant (RKL9) strain. Moreover, they also displayed stable trajectory (RMSD, RMSF) and molecular properties with consistent interaction profile in molecular dynamics simulations. </P><P> Conclusion: We anticipate that the retrieved phytochemicals can serve as the potential hits and presented findings would be helpful for the designing of malarial therapeutics.

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

Polymers ◽  
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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