ChemInform Abstract: Supramolecular Chemistry. Part 93. Electrostatic Interactions Between Positively Charged Porphyrins and Nucleotides or Amides: Buffer-Dependent Dramatic Changes of Binding Affinities and Modes.

SummaryThe interaction between GPIb and thrombin promotes platelet activation elicited via the hydrolysis of the thrombin receptor and involves structures located on the segment 238-290 within the N-terminal domain of GPIbα and the positively charged exosite 1 on thrombin. We have investigated the ability of peptides derived from the 269-287 sequence of GPIbα to interact with thrombin. Three peptides were synthesized, including Ibα 269-287 and two scrambled peptides R1 and R2 which are comparable to Ibα 269-287 with regards to their content and distribution of anionic residues. However, R2 differs from both Ibα 269-287 and R1 by the shifting of one proline from a central position to the N-terminus. By chemical cross-linking, we observed the formation of a complex between 125I-Ibα 269-287 and α-thrombin that was inhibited by hirudin, the C-terminal peptide of hirudin, sodium pyrophosphate but not by heparin. The complex did not form when γ-thrombin was substituted for α-thrombin. Ibα 269-287 produced only slight changes in thrombin amidolytic activity and inhibited thrombin binding to fibrin. R1 and R2 also formed complexes with α-thrombin, modified slightly its catalytic activity and inhibited its binding to fibrin. Peptides Ibα 269-287 and R1 inhibited platelet aggregation and secretion induced by low thrombin concentrations whereas R2 was without effect. Our results indicate that Ibα 269-287 interacts with thrombin exosite 1 via mainly electrostatic interactions, which explains why the scrambled peptides also interact with exosite 1. Nevertheless, the lack of effect of R2 on thrombin-induced platelet activation suggests that proline 280 is important for thrombin interaction with GPIb.

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Subunit assembly of hemoglobin: an important determinant of hematologic phenotype

Blood ◽

10.1182/blood.v69.1.1.bloodjournal6911 ◽

1987 ◽

Vol 69 (1) ◽

pp. 1-6 ◽

Cited By ~ 4

Author(s):

HF Bunn

Keyword(s):

Electrostatic Interactions ◽

Hemoglobin Concentration ◽

Cytoskeletal Proteins ◽

Membrane Receptors ◽

Target Cells ◽

Red Cell Membrane ◽

Alpha Beta ◽

The Difference ◽

Polypeptide Chains ◽

Positively Charged

Hemoglobin's physiologic properties depend on the orderly assembly of its subunits in erythropoietic cells. The biosynthesis of alpha- and beta-globin polypeptide chains is normally balanced. Heme rapidly binds to the globin subunit, either during translation or shortly thereafter. The formation of the alpha beta-dimer is facilitated by electrostatic attraction of a positively charged alpha-subunit to a negatively charged beta-subunit. The alpha beta-dimer dissociates extremely slowly. The difference between the rate of dissociation of alpha beta- and alpha gamma-dimers with increasing pH explains the well-known alkaline resistance of Hb F. Two dimers combine to form the functioning alpha 2 beta 2-tetramer. This model of hemoglobin assembly explains the different levels of positively charged and negatively charged mutant hemoglobins that are encountered in heterozygotes and the effect of alpha-thalassemia and heme deficiency states in modifying the level of the variant hemoglobin as well as Hb A2. Electrostatic interactions also affect the binding of hemoglobin to the cytoplasmic surface of the red cell membrane and may underlie the formation of target cells. Enhanced binding of positively charged variants such as S and C trigger a normally dormant pathway for potassium and water loss. Thus, the positive charge on beta c is responsible for the two major contributors to the pathogenesis of Hb SC disease: increased proportion of Hb S and increased intracellular hemoglobin concentration. It is likely that electrostatic interactions play an important role in the assembly of a number of other multisubunit macromolecules, including membrane receptors, cytoskeletal proteins, and DNA binding proteins.

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The C-terminal peptide of CCL21 drastically augments CCL21 activity through the dendritic cell lymph node homing receptor CCR7 by interaction with the receptor N-terminus

Cellular and Molecular Life Sciences ◽

10.1007/s00018-021-03930-7 ◽

2021 ◽

Author(s):

Astrid Sissel Jørgensen ◽

Emma Probst Brandum ◽

Jeppe Malthe Mikkelsen ◽

Klaudia A. Orfin ◽

Ditte Rahbæk Boilesen ◽

...

Keyword(s):

Lymph Node ◽

Electrostatic Interactions ◽

Immune Cell ◽

Direct Interaction ◽

Receptor Interaction ◽

Binding Model ◽

Lymph Node Homing ◽

Gating Mechanism ◽

N Terminus ◽

Positively Charged

AbstractThe endogenous chemokines CCL19 and CCL21 signal via their common receptor CCR7. CCL21 is the main lymph node homing chemokine, but a weak chemo-attractant compared to CCL19. Here we show that the 41-amino acid positively charged peptide, released through C-terminal cleavage of CCL21, C21TP, boosts the immune cell recruiting activity of CCL21 by up to 25-fold and the signaling activity via CCR7 by ~ 100-fold. Such boosting is unprecedented. Despite the presence of multiple basic glycosaminoglycan (GAG) binding motifs, C21TP boosting of CCL21 signaling does not involve interference with GAG mediated cell-surface retention. Instead, boosting is directly dependent on O-glycosylations in the CCR7 N-terminus. As dictated by the two-step binding model, the initial chemokine binding involves interaction of the chemokine fold with the receptor N-terminus, followed by insertion of the chemokine N-terminus deep into the receptor binding pocket. Our data suggest that apart from a role in initial chemokine binding, the receptor N-terminus also partakes in a gating mechanism, which could give rise to a reduced ligand activity, presumably through affecting the ligand positioning. Based on experiments that support a direct interaction of C21TP with the glycosylated CCR7 N-terminus, we propose that electrostatic interactions between the positively charged peptide and sialylated O-glycans in CCR7 N-terminus may create a more accessible version of the receptor and thus guide chemokine docking to generate a more favorable chemokine-receptor interaction, giving rise to the peptide boosting effect.

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Upper Critical Solution Temperature (UCST) Behavior of Coacervate of Cationic Protamine and Multivalent Anions

Polymers ◽

10.3390/polym11040691 ◽

2019 ◽

Vol 11 (4) ◽

pp. 691 ◽

Cited By ~ 2

Author(s):

Hyungbin Kim ◽

Byoung-jin Jeon ◽

Sangsik Kim ◽

YongSeok Jho ◽

Dong Soo Hwang

Keyword(s):

Electrostatic Interactions ◽

Solution Temperature ◽

Complex Coacervation ◽

Critical Factors ◽

Critical Solution Temperature ◽

Temperature Changes ◽

Upper Critical Solution Temperature ◽

Large Asymmetry ◽

Positively Charged ◽

Liquid Liquid Phase Separation

Complex coacervation is an emerging liquid/liquid phase separation (LLPS) phenomenon that behaves as a membrane-less organelle in living cells. Yet while one of the critical factors for complex coacervation is temperature, little analysis and research has been devoted to the temperature effect on complex coacervation. Here, we performed a complex coacervation of cationic protamine and multivalent anions (citrate and tripolyphosphate (TPP)). Both mixtures (i.e., protamine/citrate and protamine/TPP) underwent coacervation in an aqueous solution, while a mixture of protamine and sodium chloride did not. Interestingly, the complex coacervation of protamine and multivalent anions showed upper critical solution temperature (UCST) behavior, and the coacervation of protamine and multivalent anions was reversible with solution temperature changes. The large asymmetry in molecular weight between positively charged protamine (~4 kDa) and the multivalent anions (<0.4 kDa) and strong electrostatic interactions between positively charged guanidine residues in protamine and multivalent anions were likely to contribute to UCST behavior in this coacervation system.

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Effects of Substitutions of Arginine Residues on the Basic Surface of Herpes Simplex Virus UL42 Support a Role for DNA Binding in Processive DNA Synthesis

Journal of Virology ◽

10.1128/jvi.79.18.12025-12034.2005 ◽

2005 ◽

Vol 79 (18) ◽

pp. 12025-12034 ◽

Cited By ~ 18

Author(s):

John C. W. Randell ◽

Gloria Komazin ◽

Changying Jiang ◽

Charles B. C. Hwang ◽

Donald M. Coen

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Dna Binding ◽

Dna Synthesis ◽

Electrostatic Interactions ◽

Dissociation Constants ◽

Specific Effect ◽

Arginine Residues ◽

Simplex Virus ◽

Positively Charged

ABSTRACT The way that UL42, the processivity subunit of the herpes simplex virus DNA polymerase, interacts with DNA and promotes processivity remains unclear. A positively charged face of UL42 has been proposed to participate in electrostatic interactions with DNA that would tether the polymerase to a template without preventing its translocation via DNA sliding. An alternative model proposes that DNA binding by UL42 is not important for processivity. To investigate these issues, we substituted alanine for each of four conserved arginine residues on the positively charged surface. Each single substitution decreased the DNA binding affinity of UL42, with 14- to 30-fold increases in apparent dissociation constants. The mutant proteins exhibited no meaningful change in affinity for binding to the C terminus of the catalytic subunit of the polymerase, indicating that the substitutions exert a specific effect on DNA binding. The substitutions decreased UL42-mediated long-chain DNA synthesis by the polymerase in the same rank order in which they affected DNA binding, consistent with a role for DNA binding in polymerase processivity. Combining these substitutions decreased DNA binding further and impaired the complementation of a UL42 null virus in transfected cells. Additionally, using a revised mathematical model to analyze rates of dissociation of UL42 from DNAs of various lengths, we found that dissociation from internal sites, which would be the most important for tethering the polymerase, was relatively slow, even at ionic strengths that permit processive DNA synthesis by the holoenzyme. These data provide evidence that the basic surface of UL42 interacts with DNA and support a model in which DNA binding by UL42 is important for processive DNA synthesis.

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Surface Modification of Multiwalled Carbon Nanotubes with Engineered Self-Assembled RAFT Diblock Coatings

Australian Journal of Chemistry ◽

10.1071/ch13401 ◽

2014 ◽

Vol 67 (1) ◽

pp. 151 ◽

Cited By ~ 6

Author(s):

Yue Liu ◽

Xiaojuan Hao ◽

Lynne J. Waddington ◽

Jieshan Qiu ◽

Timothy C. Hughes

Keyword(s):

Carbon Nanotubes ◽

Multiwalled Carbon Nanotubes ◽

Electrostatic Interactions ◽

Diblock Copolymers ◽

Raft Polymerization ◽

Dispersion Stability ◽

Multiwalled Carbon ◽

Molecular Weights ◽

Poly Ethylene ◽

Positively Charged

A facile method to modify the surface of multiwalled carbon nanotubes (MWCNTs) via electrostatic interactions between polyelectrolytes and oxidized MWCNTs was developed. Diblock copolymers containing poly[2-(methacryloyloxy)ethyltrimethylammonium chloride] (PMETAC), a positively charged block, and poly(ethylene glycol) methacrylate (PEGMA), a neutral block, with tailored molecular weights and low polydispersities were synthesized by reversible addition–fragmentation chain transfer (RAFT) polymerization. Acid treated-MWCNTs were coated with the RAFT diblock copolymers to improve their dispersibility in aqueous phosphate buffered saline (PBS) solution. The short positively charged PMETAC block was designed to attach the block copolymers to the surface of MWCNTs via electrostatic interactions, whereas the PEGMA block improved dispersibility of the MWCNTs in aqueous solutions. Extensive screening of the diblock copolymers with different degrees of polymerization (DP) showed that the dispersion stability of the polymer-coated MWCNTs in PBS was greatly improved with increasing chain length of the PEGMA block. In particular, the MWCNTs coated with a diblock copolymer containing PEGMA (DP = 118, the longest block investigated) showed superior dispersion stability in both water and PBS solution.

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Retardation of the Molecular Rotation ofp-Nitrophenolate Ion in the Cavity of a Positively Charged Derivative of α-Cyclodextrin by Electrostatic Interactions

Chemistry Letters ◽

10.1246/cl.2000.960 ◽

2000 ◽

Vol 29 (8) ◽

pp. 960-961

Author(s):

Jalaluddin Ahmed ◽

Takuya Nagata ◽

Shinji Imaoka ◽

Yoshihisa Matsui ◽

Tatsuyuki Yamamoto

Keyword(s):

Electrostatic Interactions ◽

Molecular Rotation ◽

Charged Derivative ◽

Positively Charged

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Conformational analysis of 2,2-difluoroethylamine hydrochloride: double gauche effect

Beilstein Journal of Organic Chemistry ◽

10.3762/bjoc.10.84 ◽

2014 ◽

Vol 10 ◽

pp. 877-882 ◽

Cited By ~ 7

Author(s):

Josué M Silla ◽

Claudimar J Duarte ◽

Rodrigo A Cormanich ◽

Roberto Rittner ◽

Matheus P Freitas

Keyword(s):

Hydrogen Bond ◽

Electrostatic Interactions ◽

Fluorine Atom ◽

Theoretical Calculations ◽

Water Solution ◽

Coupling Constants ◽

Secondary Importance ◽

Gauche Effect ◽

Intramolecular Hydrogen ◽

Positively Charged

The gauche effect in fluorinated alkylammonium salts is well known and attributed either to an intramolecular hydrogen bond or to an electrostatic attraction between the positively charged nitrogen and the vicinal electronegative fluorine atom. This work reports the effect of adding a fluorine atom in 2-fluoroethylamine hydrochloride on the conformational isomerism of the resulting 2,2-difluoroethylamine chloride (2). The analysis was carried out using NMR coupling constants in D2O solution, in order to mimic the equilibrium conditions in a physiological medium, in the gas phase and in implicit water through theoretical calculations. Despite the presence of σCH→σ*CF and σCH→σ*CN interactions, which usually rule the hyperconjugative gauche effect in 1,2-disubstituted ethanes, the most important forces leading to the double gauche effect (+NH3 in the gauche relationship with both fluorine atoms) in 2 are the Lewis-type ones. Particularly, electrostatic interactions are operative even in water solution, where they should be significantly attenuated, whereas hyperconjugation and hydrogen bond have secondary importance.

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E484K mutation in SARS-CoV-2 RBD enhances binding affinity with hACE2 but reduces interactions with neutralizing antibodies and nanobodies: Binding free energy calculation studies

10.1101/2021.02.17.431566 ◽

2021 ◽

Author(s):

Wei Bu Wang ◽

Yu Liang ◽

Yu Qin Jin ◽

Jing Zhang ◽

Ji Guo Su ◽

...

Keyword(s):

Hydrogen Bonds ◽

Binding Affinity ◽

Receptor Binding ◽

Neutralizing Antibodies ◽

Electrostatic Interactions ◽

Tight Binding ◽

Energy Calculation ◽

Binding Affinities ◽

Loop Region ◽

Binding Interface

AbstractThe pandemic of the COVID-19 disease caused by SARS-CoV-2 has led to more than 100 million infections and over 2 million deaths worldwide. The progress in the developments of effective vaccines and neutralizing antibody therapeutics brings hopes to eliminate the threat of COVID-19. However, SARS-CoV-2 continues to mutate, and several new variants have been emerged. Among the various naturally-occurring mutations, the E484K mutation shared by both the 501Y.V2 and 501Y.V3 variants attracted serious concerns, which may potentially enhance the receptor binding affinity and reduce the immune response. In the present study, the molecular mechanism behind the impacts of E484K mutation on the binding affinity of the receptor-binding domain (RBD) with the receptor human angiotensin-converting enzyme 2 (hACE2) was investigated by using the molecular dynamics (MD) simulations combined with the molecular mechanics-generalized Born surface area (MMGBSA) method. Our results indicate that the E484K mutation results in more favorable electrostatic interactions compensating the burial of the charged and polar groups upon the binding of RBD with hACE2, which significantly improves the RBD-hACE2 binding affinity. Besides that, the E484K mutation also causes the conformational rearrangements of the loop region containing the mutant residue, which leads to more tight binding interface of RBD with hACE2 and formation of some new hydrogen bonds. The more tight binding interface and the new hydrogen bonds formation also contribute to the improved binding affinity of RBD to the receptor hACE2. In addition, six neutralizing antibodies and nanobodies complexed with RBD were selected to explore the effects of E484K mutation on the recognition of these antibodies to RBD. The simulation results show that the E484K mutation significantly reduces the binding affinities to RBD for most of the studied neutralizing antibodies, and the decrease in the binding affinities is mainly owing to the unfavorable electrostatic interactions caused by the mutation. Our studies revealed that the E484K mutation may improve the binding affinity between RBD and the receptor hACE2, implying more transmissibility of the E484K-containing variants, and weaken the binding affinities between RBD and the studied neutralizing antibodies, indicating reduced effectiveness of these antibodies. Our results provide valuable information for the effective vaccine development and antibody drugs design.

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