scholarly journals Correlation of N-glycan dynamics and interaction network with allosteric antigen binding and Fc receptor recognition

2021 ◽  
Author(s):  
Buyong Ma
Keyword(s):  
Radial Distance ◽  
Interaction Network ◽  
Fc Receptor ◽  
Distance Distribution ◽  
Interaction Patterns ◽  
Free Antibody ◽  
Antigen Complex ◽  
Dynamics Simulations ◽  
Carbohydrate Chains ◽  
Antibody Drug

Aim: Fragment crystallizable (Fc) glycans modulate Fc conformations and functions, and glycan may also regulate antigen recognition. In the antibody drug development, glycosylation patterns affect antibody drug characteristics and quality control. In order to provide a global feature of N-glycan interactions in response to antigen and Fc receptor bindings, the interactions among Fc N-glycans and N-glycans’ interaction with Fc CH2 and CH3 domains have been studied. Methods: Molecular dynamics simulations were used to generate conformation ensembles of free antibody, antibody-antigen complex, antibody-human Fc-gamma-receptor-I (hFcγRI) and antibody-antigen-hFcγRI, the hydrogen bonds and radial distance distribution involving N-glycans carbohydrate chains have been analyzed. Results: Two important interaction patterns have been observed. The first is the strong but non-specific interactions between two carbohydrate chains in free antibody. Secondly, it has been found that N-glycans carbohydrate chains can directly interact with CH3 domain in free antibody, and that the distance distribution between carbohydrate chains and CH3 domain clearly differentiate the free antibody, antibody-antigen complex, antibody-hFcγRI complex, and final antibody-antigen-hFcγRI complex. Conclusions: N-glycans partially acts as allosteric sensor and respond to antigen and hFcγRI binding.

scholarly journals Molecular Modeling of µ Opioid Receptor Ligands with Various Functional Properties: PZM21, SR-17018, Morphine, and Fentanyl—Simulated Interaction Patterns Confronted with Experimental Data

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4636 ◽  
Author(s):  
Sabina Podlewska ◽  
Ryszard Bugno ◽  
Lucja Kudla ◽  
Andrzej J. Bojarski ◽  
Ryszard Przewlocki
Keyword(s):  
Molecular Modeling ◽  
G Protein ◽  
Opioid Receptor ◽  
Pearson Correlation ◽  
Interaction Patterns ◽  
Receptor Ligands ◽  
Opioid Receptor Ligands ◽  
Dynamics Simulations

Molecular modeling approaches are an indispensable part of the drug design process. They not only support the process of searching for new ligands of a given receptor, but they also play an important role in explaining particular activity pathways of a compound. In this study, a comprehensive molecular modeling protocol was developed to explain the observed activity profiles of selected µ opioid receptor agents: two G protein-biased µ opioid receptor agonists (PZM21 and SR-17018), unbiased morphine, and the β-arrestin-2-biased agonist, fentanyl. The study involved docking and molecular dynamics simulations carried out for three crystal structures of the target at a microsecond scale, followed by the statistical analysis of ligand–protein contacts. The interaction frequency between the modeled compounds and the subsequent residues of a protein during the simulation was also correlated with the output of in vitro and in vivo tests, resulting in the set of amino acids with the highest Pearson correlation coefficient values. Such indicated positions may serve as a guide for designing new G protein-biased ligands of the µ opioid receptor.

scholarly journals Fold and flexibility: what can proteins' mechanical properties tell us about their folding nucleus?

2015 ◽  
Vol 12 (112) ◽  
pp. 20150876 ◽  
Author(s):  
Sophie Sacquin-Mora
Keyword(s):  
Mechanical Properties ◽  
Brownian Dynamics ◽  
Protein Structures ◽  
Interaction Network ◽  
Sequence Alignments ◽  
Multiple Sequence ◽  
Multiple Sequence Alignments ◽  
Folding Nucleus ◽  
Dynamics Simulations ◽  
Brownian Dynamics Simulations

The determination of a protein's folding nucleus, i.e. a set of native contacts playing an important role during its folding process, remains an elusive yet essential problem in biochemistry. In this work, we investigate the mechanical properties of 70 protein structures belonging to 14 protein families presenting various folds using coarse-grain Brownian dynamics simulations. The resulting rigidity profiles combined with multiple sequence alignments show that a limited set of rigid residues, which we call the consensus nucleus, occupy conserved positions along the protein sequence. These residues' side chains form a tight interaction network within the protein's core, thus making our consensus nuclei potential folding nuclei. A review of experimental and theoretical literature shows that most (above 80%) of these residues were indeed identified as folding nucleus member in earlier studies.

scholarly journals Multivalent and Bidirectional Binding of Transcriptional Transactivation Domains to the MED25 Coactivator

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1205
Author(s):  
Heather M. Jeffery ◽  
Robert O. J. Weinzierl
Keyword(s):  
Transcriptional Activation ◽  
Site Directed Mutagenesis ◽  
Viral Gene ◽  
Interaction Patterns ◽  
Hydrophobic Residues ◽  
Activation Domains ◽  
Intrinsically Disordered ◽  
Transactivation Domains ◽  
Transcriptional Activation Domains ◽  
Dynamics Simulations

The human mediator subunit MED25 acts as a coactivator that binds the transcriptional activation domains (TADs) present in various cellular and viral gene-specific transcription factors. Previous studies, including on NMR measurements and site-directed mutagenesis, have only yielded low-resolution models that are difficult to refine further by experimental means. Here, we apply computational molecular dynamics simulations to study the interactions of two different TADs from the human transcription factor ETV5 (ERM) and herpes virus VP16-H1 with MED25. Like other well-studied coactivator-TAD complexes, the interactions of these intrinsically disordered domains with the coactivator surface are temporary and highly dynamic (‘fuzzy’). Due to the fact that the MED25 TAD-binding region is organized as an elongated cleft, we specifically asked whether these TADs are capable of binding in either orientation and how this could be achieved structurally and energetically. The binding of both the ETV5 and VP16-TADs in either orientation appears to be possible but occurs in a conformationally distinct manner and utilizes different sets of hydrophobic residues present in the TADs to drive the interactions. We propose that MED25 and at least a subset of human TADs specifically evolved a redundant set of molecular interaction patterns to allow binding to particular coactivators without major prior spatial constraints.

scholarly journals Structure of full-length human phenylalanine hydroxylase in complex with tetrahydrobiopterin

2019 ◽  
Vol 116 (23) ◽  
pp. 11229-11234 ◽  
Author(s):  
Marte Innselset Flydal ◽  
Martín Alcorlo-Pagés ◽  
Fredrik Gullaksen Johannessen ◽  
Siseth Martínez-Caballero ◽  
Lars Skjærven ◽  
...  
Keyword(s):  
Phenylalanine Hydroxylase ◽  
Genetic Disorder ◽  
Interaction Network ◽  
Salt Bridge ◽  
Full Length ◽  
Site Directed Mutagenesis ◽  
Pharmacological Chaperone ◽  
Key Enzyme ◽  
The Stability ◽  
Dynamics Simulations

Phenylalanine hydroxylase (PAH) is a key enzyme in the catabolism of phenylalanine, and mutations in this enzyme cause phenylketonuria (PKU), a genetic disorder that leads to brain damage and mental retardation if untreated. Some patients benefit from supplementation with a synthetic formulation of the cofactor tetrahydrobiopterin (BH4) that partly acts as a pharmacological chaperone. Here we present structures of full-length human PAH (hPAH) both unbound and complexed with BH4 in the precatalytic state. Crystal structures, solved at 3.18-Å resolution, show the interactions between the cofactor and PAH, explaining the negative regulation exerted by BH4. BH4 forms several H-bonds with the N-terminal autoregulatory tail but is far from the catalytic FeII. Upon BH4 binding a polar and salt-bridge interaction network links the three PAH domains, explaining the stability conferred by BH4. Importantly, BH4 binding modulates the interaction between subunits, providing information about PAH allostery. Moreover, we also show that the cryo-EM structure of hPAH in absence of BH4 reveals a highly dynamic conformation for the tetramers. Structural analyses of the hPAH:BH4 subunits revealed that the substrate-induced movement of Tyr138 into the active site could be coupled to the displacement of BH4 from the precatalytic toward the active conformation, a molecular mechanism that was supported by site-directed mutagenesis and targeted molecular dynamics simulations. Finally, comparison of the rat and human PAH structures show that hPAH is more dynamic, which is related to amino acid substitutions that enhance the flexibility of hPAH and may increase the susceptibility to PKU-associated mutations.

scholarly journals Interaction Patterns for Staggered Assembly of Fibrils from Semiflexible Chains

Symmetry ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1926
Author(s):  
Arnoud Jongeling ◽  
Carsten Svaneborg ◽  
Renko de Vries
Keyword(s):  
Interaction Energy ◽  
Self Assembly ◽  
Compact Objects ◽  
The Self ◽  
Interaction Patterns ◽  
Interaction Energies ◽  
Colloidal Interactions ◽  
Dynamics Simulations ◽  
Positively Charged ◽  
Simple Interaction

The design of colloidal interactions to achieve target self-assembled structures has especially been done for compact objects such as spheres with isotropic interaction potentials, patchy spheres and other compact objects with patchy interactions. Inspired by the self-assembly of collagen-I fibrils and intermediate filaments, we here consider the design of interaction patterns on semiflexible chains that could drive their staggered assembly into regular (para)crystalline fibrils. We consider semiflexible chains composed of a finite number of types of interaction beads (uncharged hydrophilic, hydrophobic, positively charged and negatively charged) and optimize the sequence of these interaction beads with respect to the interaction energy of the semiflexible chains in a number of target-staggered crystalline packings. We find that structures with the lowest interaction energies, that form simple lattices, also have low values of L/D (where L is chain length and D is stagger). In the low interaction energy sequences, similar types of interaction beads cluster together to form stretches. Langevin Dynamics simulations confirm that semiflexible chains with optimal sequences self-assemble into the designed staggered (para)crystalline fibrils. We conclude that very simple interaction patterns should suffice to drive the assembly of long semiflexible chains into staggered (para)crystalline fibrils.

scholarly journals THE ESTIMATION OF CIRCULATING ANTIBODY-ANTIGEN COMPLEX

1953 ◽  
Vol 98 (5) ◽  
pp. 451-460 ◽  
Author(s):  
L. A. Sternberger ◽  
Frank Maltaner ◽  
Jacob DeWeerdt
Keyword(s):  
Free Antibody ◽  
Antigen Complex ◽  
Antigen Antibody ◽  
Free Antigen ◽  
Circulating Antibody

Immune sera were subjected to treatment with alkali in the cold to cause dissociation of antigen-antibody complexes. Precipitates and a capacity to fix complement developed in some of these sera subsequent to such treatment. The specific immunologic nature of these phenomena and their observation in relation to disappearance of free antigen and appearance of free antibody in circulation are discussed. The phenomena observed appear to be consistent with the assumption that a circulating antibody-antigen complex is revealed as a result of treatment.

Understanding neighborhood isolation through spatial interaction network analysis using location big data

2019 ◽  
Vol 52 (6) ◽  
pp. 1027-1031 ◽  
Author(s):  
Timothy Prestby ◽  
Joseph App ◽  
Yuhao Kang ◽  
Song Gao
Keyword(s):  
Network Analysis ◽  
Large Scale ◽  
Spatial Interaction ◽  
Interaction Network ◽  
Location Based Services ◽  
Interaction Patterns ◽  
Individual Level ◽  
Mobility Data ◽  
The Usa ◽  
Hidden Biases

Hidden biases of racial and socioeconomic preferences shape residential neighborhoods throughout the USA. Thereby, these preferences shape neighborhoods composed predominantly of a particular race or income class. However, the assessment of spatial extent and the degree of isolation outside the residential neighborhoods at large scale is challenging, which requires further investigation to understand and identify the magnitude and underlying geospatial processes. With the ubiquitous availability of location-based services, large-scale individual-level location data have been widely collected using numerous mobile phone applications and enable the study of neighborhood isolation at large scale. In this research, we analyze large-scale anonymized smartphone users’ mobility data in Milwaukee, Wisconsin, to understand neighborhood-to-neighborhood spatial interaction patterns of different racial classes. Several isolated neighborhoods are successfully identified through the mobility-based spatial interaction network analysis.

Increment in Drug Loading on an Antibody–Drug Conjugate Increases Its Binding to the Human Neonatal Fc Receptor in Vitro

2016 ◽  
Vol 13 (4) ◽  
pp. 1405-1412 ◽  
Author(s):  
Guillaume Brachet ◽  
Renaud Respaud ◽  
Christophe Arnoult ◽  
Corinne Henriquet ◽  
Christine Dhommée ◽  
...  
Keyword(s):  
Drug Loading ◽  
Fc Receptor ◽  
Neonatal Fc Receptor ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Antibody Drug

scholarly journals TiCl4 Dissolved in Ionic Liquid Mixtures from Аb Initio Molecular Dynamics Simulations

Molecules ◽  
2020 ◽  
Vol 26 (1) ◽  
pp. 79
Author(s):  
Lars Esser ◽  
Roberto Macchieraldo ◽  
Roman Elfgen ◽  
Melanie Sieland ◽  
Bernd Michael Smarsly ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Ionic Liquid ◽  
Molecular Dynamics Simulations ◽  
Interaction Network ◽  
Liquid Mixtures ◽  
Distribution Functions ◽  
Ab Initio Molecular Dynamics ◽  
Complex Interactions ◽  
Dynamics Simulations ◽  
Anion Interaction

To gain a deeper understanding of the TiCl4 solvation effects in multi-component ionic liquids, we performed ab initio molecular dynamics simulations of 1-butyl-3-methylimidazolium [C4C1Im]+, tetrafluoroborate [BF4]−, chloride [Cl]− both with and without water and titanium tetrachloride TiCl4. Complex interactions between cations and anions are observed in all investigated systems. By further addition of water and TiCl4 this complex interaction network is extended. Observations of the radial distribution functions and number integrals show that water and TiCl4 not only compete with each other to interact mainly with [Cl]−, which strongly influences the cation-[BF4]− interaction, but also interact with each other, which leads to the fact that in certain systems the cation-anion interaction is enhanced. Further investigations of the Voronoi polyhedra analysis have demonstrated that water has a greater impact on the nanosegregated system than TiCl4 which is also due to the fact of the shear amount of water relative to all other components and its higher mobility compared to TiCl4. Overall, the polar network of the IL mixture collapses by including water and TiCl4. In the case of [Cl]− chloride enters the water continuum, while [BF4]− remains largely unaffected, which deeply affects the interaction of the ionic liquid (IL) network.

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