scholarly journals 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

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.

scholarly journals Climbing up and down binding landscapes: a high-throughput study of mutational effects in homologous protein-protein complexes

2020 ◽  
Author(s):  
Michael Heyne ◽  
Jason Shirian ◽  
Itay Cohen ◽  
Yoav Peleg ◽  
Evette S. Radisky ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Protein Interactions ◽  
Enzyme Inhibitor ◽  
Binding Free Energy ◽  
Hot Spot ◽  
Cold Spot ◽  
Binding Affinities ◽  
High Affinity ◽  
Binding Interface ◽  
Biological Complexes

AbstractEach protein-protein interaction (PPI) has evolved to possess binding affinity that is compatible with its cellular function. As such, cognate enzyme/inhibitor interactions frequently exhibit very high binding affinities, while structurally similar non-cognate PPIs possess substantially weaker binding affinities. To understand how slight differences in sequence and structure could lead to drastic changes in PPI binding free energy (ΔΔGbind), we study three homologous PPIs that span nine orders of magnitude in binding affinity and involve a serine protease interacting with an inhibitor BPTI. Using state-of-the-art methodology that combines protein randomization and affinity sorting coupled to next-generation sequencing and data normalization, we report quantitative binding landscapes consisting of ΔΔGbind values for the three PPIs, gleaned from tens of thousands of single and double mutations in the BPTI binding interface. We demonstrate that the three homologous PPIs possess drastically different binding landscapes and lie at different points in respect to the landscape maximum. Furthermore, the three PPIs demonstrate distinct patterns of coupling energies between two simultaneous mutations that depend not only on positions involved but also on the nature of the mutation. Interestingly, we find that in all three PPIs positive epistasis is frequently observed at hot-spot positions where mutations lead to loss of high affinity, while conversely negative epistasis is observed at cold-spot positions, where mutations lead to affinity enhancement. The new insights on PPI evolution revealed in this study will be invaluable in understanding evolution of other biological complexes and can greatly facilitate design of novel high-affinity protein inhibitors.SignificanceProtein-protein interactions (PPIs) have evolved to display binding affinities that can support their function. As such, cognate and non-cognate PPIs could be highly similar structurally but exhibit huge differences in binding affinities. To understand this phenomenon, we studied the effect of tens of thousands of single and double mutations on binding affinity of three homologous protease-inhibitor complexes. We show that binding landscapes of the three complexes are strikingly different and depend on the PPI evolutionary optimality. We observe different patterns of couplings between mutations for the three PPIs with negative and positive epistasis appearing most frequently at hot-spot and cold-spot positions, respectively. The evolutionary trends observed here are likely to be universal to all biological complexes in the cell.

scholarly journals The expression of hACE2 receptor protein and its involvement in SARS-CoV-2 entry, pathogenesis, and its application as potential therapeutic target

Tumor Biology ◽  
2021 ◽  
Vol 43 (1) ◽  
pp. 177-196
Author(s):  
Lobna Al-Zaidan ◽  
Sarra Mestiri ◽  
Afsheen Raza ◽  
Maysaloun Merhi ◽  
Varghese Philipose Inchakalody ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Receptor Binding ◽  
Virus Disease ◽  
Respiratory Illness ◽  
Host Cells ◽  
World Health ◽  
Receptor Protein ◽  
Unknown Etiology ◽  
Spike Glycoprotein ◽  
Binding Interface

Pneumonia cases of unknown etiology in Wuhan, Hubei province, China were reported to the World Health Organization on 31st of December 2019. Later the pathogen was reported to be a novel coronavirus designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes Corona virus disease 2019 (COVID-19). The disease outspread was followed by WHO declaration of COVID-19 pandemic as a “Public Health Emergency of International Concern”. SARS-CoV-2 is a novel pathogenic beta coronavirus that infects humans causing severe respiratory illness. However, multifarious factors can contribute to the susceptibility to COVID-19 related morbidity and mortality such as age, gender, and underlying comorbidities. Infection initiates when viral particles bind to the host cell surface receptors where SARS-CoV-2 spike glycoprotein subunit 1 binds to the Angiotensin Converting Enzyme 2 (ACE2). It is of importance to mention that SARS-CoV and SARS-CoV-2 viruses’ mediate entry into the host cells via ACE2 receptor which might be correlated with the structural similarity of spike glycoprotein subunit 1 of both SARS viruses. However, the structural binding differs, whereas ACE2 receptor binding affinity with SARS-CoV-2 is 4 folds higher than that with SARS-CoV. Moreover, amino acids sequence divergence between the two S glycoproteins might be responsible for differential modulations of the specific immune response to both viruses. Identification of different aspects such as binding affinity, differential antigenic profiles of S-glycoproteins, and ACE2 mutations might influence the investigation of potential therapeutic strategies targeting SARS-CoV-2/ACE2 binding interface. In this review, we aim to elaborate on the expression of hACE2 receptor protein and its binding with SARS-CoV-2 S1 subunit, the possible immunogenic sequences of spike protein, effect of ACE 2 polymorphism on viral binding, and infectivity/susceptibility to disease. Furthermore, targeting of hACE2 receptor binding with SARS-CoV-2 S1 subunit via various mechanisms will be discussed to understand its role in therapeutics.

scholarly journals Docking of Platinum Compounds on Cube Rhombellane Functionalized Homeomorphs

Symmetry ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 749
Author(s):  
Beata Szefler ◽  
Przemysław Czeleń
Keyword(s):  
Hydrogen Bond ◽  
Hydrogen Bonds ◽  
Binding Affinity ◽  
Fullerene C60 ◽  
C60 Fullerene ◽  
Binding Affinities ◽  
Hydrogen Bond Network ◽  
Platinum Compounds ◽  
Anti Cancer ◽  
Bond Network

Platinum compounds are anti-cancer drugs and can bind to canonical purine bases, mainly guanine, found within double helical DNA. Platinum compounds can be transferred directly to pathologically altered sites in a specific and site-oriented manner by nanocarriers as potential nanocarriers for carboplatin. Two types of nanostructures were used as potential nanocarriers for carboplatin, the first were functionalized C60 fullerene molecules and the second were rhombellanes. The analyzed nanostructures show considerable symmetry, which affects the affinity of the studied nanocarriers and ligands. Thus symmetry of nanostructures affects the distribution of binding groups on their surface. After the docking procedure, analysis of structural properties revealed many interesting features. In all described cases, binding affinities of complexes of platinum compounds with functionalized fullerene C60 are higher compared with affinities of complexes of platinum compounds with rhombellane structures. All platinum compounds easily create complexes with functionalized fullerene C60, CID_16156307, and at the same time show the highest binding affinity. The binding affinities of lobaplatin and heptaplatin are higher compared with oxaliplatin and nedaplatin. The high value of binding affinity and equilibrium constant K is correlated with creation of strong and medium hydrogen bonds or is correlated with forming a hydrogen bond network. The performed investigations enabled finding nanocarriers for lobaplatin, heptaplatin, oxaliplatin and nedaplatin molecules.

scholarly journals Graphic representation of pharmacology: Development of an alternative model

2017 ◽  
Vol 7 (5) ◽  
pp. 201-206 ◽  
Author(s):  
Stephen R. Saklad
Keyword(s):  
Binding Affinity ◽  
Receptor Binding ◽  
Functional Data ◽  
Binding Affinities ◽  
Inverse Agonists ◽  
Receptor Sites ◽  
Binding Data ◽  
And Function ◽  
Pie Chart

Abstract Introduction: Providing clinicians with an easy to grasp and understandable representation of pharmacology is important to allow optimal clinical decisions to be made. Two of the most clinically relevant dimensions are receptor binding affinity and functional activity. The binding affinity for an agonist is described by the dissociation constant (KA), and an antagonist by the inhibition constant (Ki). Functionally, medications can act as superagonists, agonists, partial agonists, antagonists, partial inverse agonists, or inverse agonists at several receptor sites, transporters, or ion channels. Comprehending the differences between agents is complicated by the number and types of binding sites. Methods: Binding and functional data are obtained from primary literature, product labels, human cloned receptor binding, and other sources. Binding affinities are converted into ratios relative to the putative primary receptor for that category of agent. Antipsychotic binding is referenced to dopamine type 2 long (D2L) receptor binding. Binding affinity ratios (BARs) generate a 6-spoked diagram, with D2L as the hub. The most avidly bound sites are the spokes, and the disk diameter represents the BAR. Where functional data are available, they are shown as a pie chart shading the binding site's disk. Results: Binding and function diagrams are shown for the antipsychotics where binding data are available and are compared to previous methods of pharmacologic comparisons of antipsychotics. Discussion: Use of graphic models of psychotropic pharmacology improves clinician comprehension and may serve as an aid to improve rational therapeutics and patient outcomes.

scholarly journals Enhancement of SARS-CoV-2 Receptor Binding Domain -CR3022 Human Antibody Binding Affinity via in Silico Engineering Approach

2020 ◽  
Author(s):  
Fateme Sefid ◽  
Zahra Payandeh ◽  
Ghasem Azamirad ◽  
Behzad Mansoori ◽  
Behzad Baradaran ◽  
...  
Keyword(s):  
Amino Acids ◽  
Binding Affinity ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Affinity Maturation ◽  
Binding Domain ◽  
Human Antibody ◽  
Receptor Binding Domain ◽  
Receptor Binding Site ◽  
Specificity And Sensitivity

Abstract Background: The nCoV-2019 is a cause of COVID-19 disease. The surface spike glycoprotein (S), which is necessary for virus entry through the intervention of the host receptor and it mediates virus-host membrane fusion, is the primary coronavirus antigen (Ag). The angiotensin-converting enzyme 2 (ACE2) is reported to be the effective human receptor for SARS-CoVs 2. ACE2 receptor can be prevented by neutralizing antibodies (nAbs) such as CR3022 targeting the virus receptor-binding site. Considering the importance of computational docking, and affinity maturation we aimed to find the important amino acids of the CR3022 antibody (Ab). These amino acids were then replaced by other amino acids to improve Ab-binding affinity to a receptor-binding domain (RBD) of the 2019-nCoV spike protein. Finally, we measured the binding affinity of Ab variants to the Ag. Result: Our findings disclosed that several variant mutations could successfully improve the characteristics of the Ab binding compared to the normal antibodies. Conclusion: The modified antibodies may be possible candidates for stronger affinity binding to Ags which in turn can affect the specificity and sensitivity of antibodies.

scholarly journals SARS-CoV-2 Omicron Variant: ACE2 Binding, Cryo-EM Structure of Spike Protein-ACE2 Complex and Antibody Evasion

2021 ◽  
Author(s):  
Dhiraj Mannar ◽  
James W. Saville ◽  
Xing Zhu ◽  
Shanti S. Srivastava ◽  
Alison M. Berezuk ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Hydrogen Bonds ◽  
Binding Affinity ◽  
Spike Protein ◽  
Strong Interactions ◽  
Binding Affinities ◽  
Salt Bridges ◽  
The World

The newly reported Omicron variant is poised to replace Delta as the most rapidly spread SARS-CoV-2 variant across the world. Cryo-EM structural analysis of the Omicron variant spike protein in complex with human ACE2 reveals new salt bridges and hydrogen bonds formed by mutated residues R493, S496 and R498 in the RBD with ACE2. These interactions appear to compensate for other Omicron mutations such as K417N known to reduce ACE2 binding affinity, explaining our finding of similar biochemical ACE2 binding affinities for Delta and Omicron variants. Neutralization assays show that pseudoviruses displaying the Omicron spike protein exhibit increased antibody evasion, with greater evasion observed in sera obtained from unvaccinated convalescent patients as compared to doubly vaccinated individuals (8- vs 3-fold). The retention of strong interactions at the ACE2 interface and the increase in antibody evasion are molecular factors that likely contribute to the increased transmissibility of the Omicron variant.

scholarly journals 2,3-Dibutoxynaphthalene-based tetralactam macrocycles for recognizing precious metal chloride complexes

2019 ◽  
Vol 15 ◽  
pp. 1460-1467 ◽  
Author(s):  
Li-Li Wang ◽  
Yi-Kuan Tu ◽  
Huan Yao ◽  
Wei Jiang
Keyword(s):  
Hydrogen Bonds ◽  
Precious Metal ◽  
Electrostatic Interactions ◽  
Fluorescent Sensor ◽  
Coordination Complexes ◽  
Metal Chloride ◽  
Binding Affinities ◽  
Chloride Complexes ◽  
Square Planar ◽  
Intramolecular Hydrogen

Two new tetralactam macrocycles with 2,3-dibutoxynaphthalene groups as sidewalls have been synthesized and characterized. The macrocycle containing isophthalamide bridges can bind square-planar chloride coordination complexes of gold(III), platinum(II), and palladium(II) in CDCl3, while the macrocycle with 2,6-pyridine dicarboxamide bridging units cannot. This may be due to the shrunken cavity caused by intramolecular hydrogen bonds in the latter tetralactam macrocycle. The binding of the isophthalamide-based macrocycle is mainly driven by hydrogen bonds and electrostatic interactions. This naphthalene-based macrocycle has similar binding affinities to all the three abovementioned precious metal chloride complexes. This is in contrast to the fact that the tetralactam macrocycle with anthracene as the sidewalls only show good binding affinities to AuCl4 −. The superior binding to all three complexes may be due to the conformational diversity of the naphthalene-based macrocycle, which make it conformationally adaptive to maximize the binding affinities. In addition, the macrocycle shows fluorescent quenching when adding the chloride metal complexes in its solution and may be used as a fluorescent sensor for the detection of these coordination complexes.

Mutation-induced Changes in the Receptor-binding Interface of the SARS-CoV-2 Delta Variant B.1.617.2 and Implications for Immune Evasion

2021 ◽  
Author(s):  
Prabin Baral ◽  
Nisha Bhattarai ◽  
Md Lokman Hossen ◽  
Vitalii Stebliankin ◽  
Bernard Gerstman ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Immune Evasion ◽  
Genetic Variants ◽  
Neutralizing Antibodies ◽  
Structural Changes ◽  
Spike Protein ◽  
Sharp Rise ◽  
Stable Conformation ◽  
Binding Interface ◽  
Induced Changes

While the vaccination efforts against SARS-CoV-2 infections are ongoing worldwide, new genetic variants of the virus are emerging and spreading. Following the initial surges of the Alpha (B.1.1.7) and the Beta (B.1.351) variants, a more infectious Delta variant (B.1.617.2) is now surging, further deepening the health crises caused by the pandemic. The sharp rise in cases attributed to the Delta variant has made it especially disturbing and is a variant of concern. Fortunately, current vaccines offer protection against known variants of concern, including the Delta variant. However, the Delta variant has exhibited some ability to dodge the immune system as it is found that neutralizing antibodies from prior infections or vaccines are less receptive to binding with the Delta spike protein. Here, we investigated the structural changes caused by the mutations in the Delta variant's receptor-binding interface and explored the effects on binding with the ACE2 receptor as well as with neutralizing antibodies. We find that the receptor-binding beta-loop-beta motif adopts an altered but stable conformation causing separation in some of the antibody binding epitopes. Our study shows reduced binding of neutralizing antibodies and provides a possible mechanism for the immune evasion exhibited by the Delta variant.

scholarly journals Inefficient Transmission of H5N1 Influenza Viruses in a Ferret Contact Model

2007 ◽  
Vol 81 (13) ◽  
pp. 6890-6898 ◽  
Author(s):  
Hui-Ling Yen ◽  
Aleksandr S. Lipatov ◽  
Natalia A. Ilyushina ◽  
Elena A. Govorkova ◽  
John Franks ◽  
...  
Keyword(s):  
Hong Kong ◽  
Binding Affinity ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Clinical Signs ◽  
Influenza Viruses ◽  
Contact Model ◽  
Virus Shedding ◽  
H5n1 Influenza

ABSTRACT The abilities to infect and transmit efficiently among humans are essential for a novel influenza A virus to cause a pandemic. To evaluate the pandemic potential of widely disseminated H5N1 influenza viruses, a ferret contact model using experimental groups comprised of one inoculated ferret and two contact ferrets was used to study the transmissibility of four human H5N1 viruses isolated from 2003 to 2006. The effects of viral pathogenicity and receptor binding specificity (affinity to synthetic sialosaccharides with α2,3 or α2,6 linkages) on transmissibility were assessed. A/Vietnam/1203/04 and A/Vietnam/JP36-2/05 viruses, which possess “avian-like” α2,3-linked sialic acid (SA) receptor specificity, caused neurological symptoms and death in ferrets inoculated with 103 50% tissue culture infectious doses. A/Hong Kong/213/03 and A/Turkey/65-596/06 viruses, which show binding affinity for “human-like” α2,6-linked SA receptors in addition to their affinity for α2,3-linked SA receptors, caused mild clinical symptoms and were not lethal to the ferrets. No transmission of A/Vietnam/1203/04 or A/Turkey/65-596/06 virus was detected. One contact ferret developed neutralizing antibodies to A/Hong Kong/213/03 but did not exhibit any clinical signs or detectable virus shedding. In two groups, one of two naïve contact ferrets had detectable virus after 6 to 8 days when housed together with the A/Vietnam/JP36-2/05 virus-inoculated ferrets. Infected contact ferrets showed severe clinical signs, although little or no virus was detected in nasal washes. This limited virus shedding explained the absence of secondary transmission from the infected contact ferret to the other naïve ferret that were housed together. Our results suggest that despite their receptor binding affinity, circulating H5N1 viruses retain molecular determinants that restrict their spread among mammalian species.

scholarly journals A Theoretical Study of the Relationships between Electronic Structure and CB1 and CB2 Cannabinoid Receptor Binding Affinity in a Group of 1-Aryl-5-(1-H-pyrrol-1-yl)-1-H-pyrazole-3-carboxamides

2014 ◽  
Vol 2014 ◽  
pp. 1-15
Author(s):  
Francisco Salgado-Valdés ◽  
Juan S. Gómez-Jeria
Keyword(s):  
Binding Affinity ◽  
Receptor Binding ◽  
Theoretical Study ◽  
Cannabinoid Receptor ◽  
Geometry Optimization ◽  
Wave Functions ◽  
Binding Affinities ◽  
Full Geometry Optimization ◽  
Receptor Binding Affinity ◽  
Reactivity Indices

We report the results of a search for model-based relationships between hCB1 and hCB2 receptor binding affinity and molecular structure for a group of 1-aryl-5-(1-H-pyrrol-1-yl)-1-H-pyrazole-3-carboxamides. The wave functions and local atomic reactivity indices were obtained at the B3LYP/6-31G(d,p) levels of theory with full geometry optimization. Interaction pharmacophores were generated for both receptors. The main conclusions of this work are as follows. (1) We obtained statistically significant equations relating the variation of hCB1 and hCB2 receptor binding affinities with the variation of definite sets of local atomic reactivity indices. (2) The interaction of the molecules with the hCB1 and hCB2 receptors seems to be highly complex and mainly orbital controlled. (3) The interaction mechanisms seem to be different for each type of receptor. This study, contrarily to the statistically backed ones, is able to provide a microscopic insight of the mechanisms involved in the binding process.

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