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 Improved binding affinity of the Omicron's spike protein with hACE2 receptor is the key factor behind its increased virulence

2021 ◽  
Author(s):  
Rajender Kumar ◽  
Murugan Natarajan Arul ◽  
Vaibhav Srivastava
Keyword(s):  
Free Energy ◽  
Hydrogen Bonding ◽  
Binding Affinity ◽  
Electrostatic Interactions ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Spike Protein ◽  
Strong Interactions ◽  
Salt Bridges ◽  
New Variant

The new variant of SARS-CoV-2, Omicron, has been quickly spreading in many countries worldwide. Compared to the original virus, Omicron is characterized by several mutations in its genomic region, including spike protein's receptor-binding domain (RBD). We have computationally investigated the interaction between RBD of both wild-type and omicron variants with hACE2 receptor using molecular dynamics and MM-GBSA based binding free energy calculations. The mode of the interaction between Omicron's RBD to the human ACE2 (hACE2) receptor is similar to the original SARS-CoV-2 RBD except for a few key differences. The bind-ing free energy difference shows that the spike protein of Omicron has increased binding affinity for the hACE-2 receptor. The mutated residues in the RBD showed strong interactions with a few amino acid residues of the hACE2. More specifically, strong electrostatic interactions (salt bridges) and hydrogen bonding were observed between R493 and R498 residues of the Omicron RBD with D30/E35 and D38 residues of the hACE2, respectively. Other mutated amino acids in the Omicron RBD, e.g. S496 and H505, also exhibited hydrogen bonding with the hACE2 receptor. The pi-stacking interaction was also observed between tyrosine residues (RBD-Tyr501: hACE2-Tyr41) in the complex, which contributes majorly to binding free energies suggesting this as one of the key interactions stabilizing the complex formation. The structural insights of RBD:hACE2 complex, their binding mode information and residue wise contributions to binding free energy provide insight on the increased transmissibility of Omicron and pave the way to design and optimize novel antiviral agents.

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 Harnessing the Sars-cov-2 Spike Protein Binding Affinity to Ace2 Receptor Through Narcotinic Compounds Combined With Adjuvants: an in Silico Insight

2021 ◽  
Author(s):  
Saeedeh Mohammadi ◽  
Esmail Doustkhah ◽  
Nader Sakhaee ◽  
Ayoub Esmailpour ◽  
Mohammad Esmailpour
Keyword(s):  
Binding Affinity ◽  
In Silico ◽  
Muramyl Dipeptide ◽  
Docking Studies ◽  
Spike Protein ◽  
Binding Affinities ◽  
Narcotic Analgesics ◽  
S Protein ◽  
Suitable Combination ◽  
Spike Proteins

Abstract Protein products of SARS-CoV-2 spike (S) coding gene sequence, were all analyzed and compared to other SARS-CoV S proteins to elucidate structural similarities of spike proteins. A homology modeling of SARS-CoV-2 S protein was obtained and used in molecular docking studies to find binding affinities of spike protein for angiotensin-converting enzyme 2 (ACE2). The two most important binding sites of S protein, namely, RBD and CTD, critically responsible for binding interactions, were identified. Finally, binding affinity of RBD and CTD domains of S protein with narcotic analgesics are studied. Moreover, interactions of ACE2 receptor- S protein with narcotic compounds when mixed with small molecule adjuvants to improve the immune response and increase the efficacy of potential vaccines, were taken into consideration. In-silico results suggest that the combination of narcotine hemiacetal with mannide monooleate shows a stronger binding affinity with CTD, while carprofen-muramyl dipeptide and squalene have stronger binding affinities for the RBD portion of S protein. Thus, a suitable combination of these narcotic is proposed to yield potent site-blocking efficacy for ACE2 receptor against SARS-CoV-2 spike proteins.

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.

Docking Studies of Usnic Acid and Sodium Usnate on SARS CoV-2 Main Protease and Spike Protein RBD

2020 ◽  
Author(s):  
Roopa Guthappa
Keyword(s):  
Infectious Disease ◽  
Antiviral Agents ◽  
Usnic Acid ◽  
Docking Studies ◽  
Spike Protein ◽  
Binding Affinities ◽  
Herbal Supplements ◽  
Main Protease ◽  
The World ◽  
Mouth Wash

<p><b>SARS CoV-2 a pandemic influenza like infectious disease emerged in December 2019 has spread throughout the world within few months. Scientists are trying their best to find medicine and vaccine. Usnic acid and its derivatives as herbal supplements are widely used as mouth wash, cosmetics, antiviral agents. In this study, usnic acid and its derivative-sodium usnate in comparison with favipiravir are docked with main protease and spike protein RBD </b><b>6M0J of SARS Cov-2. Usnic acid and sodium usnate exhibit better binding affinities for main protease and spike RBD. The data has been compared with favipiravir. Favipiravir, usnic acid, sodium usnate shows binding affinity of -4.25, -8.05 and -8.55 kcal/mol respectively with main protease. While favipiravir, usnic acid and sodium usnate exhibit binding affinities of -4.25, -6.02 and -6.53 kcal/mol with spike RBD respectively. One of the interesting features is that the inhibition constant values of usnic acid is 1.27 µM and sodium usnate is 539.86 nM in comparison to favipiravir (764.13 µM) with main protease. </b></p>

scholarly journals Docking of Polyethylenimines Derivatives on Cube Rhombellane Functionalized Homeomorphs

Symmetry ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1048 ◽  
Author(s):  
Beata Szefler ◽  
Przemysław Czeleń
Keyword(s):  
Hydrogen Bonds ◽  
Binding Constants ◽  
Drug Carriers ◽  
Fullerene C60 ◽  
Reference Structure ◽  
Binding Affinities ◽  
Important Goal ◽  
Polymeric Networks ◽  
The World ◽  
Fullerene Complexes

Nowadays, in the world of science, an important goal is to create new nanostructures that may act as potential drug carriers. Among different, real or hypothetical, polymeric networks, rhombellanes are very promising and, therefore, attempts were made to deposit polyethylenimines as possible nano-drug complexes on the cube rhombellane homeomorphs surface. For the search of ligand–fullerene interactions, was used AutoDockVina software. As a reference structure, the fullerene C60 was used. After the docking procedure, the ligands–fullerenes interactions were tested. The important factor determining the mutual affinity of the tested ligands and nanocarriers is the symmetry of the analyzed nanostructures. Here, this feature has the influence on the distribution of such groups like donors and acceptors of hydrogen bonds on the surface of nanoparticles. We calculated the best binding affinities of ligands, values of binding constants and differences relative to C60 molecules. The best binding efficiency was found for linear ligands. It was also found that the shorter the molecule, the better the binding performance, the more the particle grows and the lower the yield. Small structures of ligands react easily with small structures of nanoparticles. The highest positive percentage deviations were obtained for ligand–fullerene complexes showing the highest binding energy values. Detailed analysis of structural properties after docking showed that the values of affinity of the studied indolizine ligands to the rhombellanes surface are correlated with the strength/length of hydrogen bonds formed between them.

scholarly journals Structural Analysis And Molecular Characteristics of SARSCoV-2 Spike Protein Following S494P Point Mutation: Molecular Dynamics Study

2021 ◽  
Author(s):  
Mehr Ali Mahmood Janlou ◽  
Hassan sahebjamee ◽  
Shademan Shokravi
Keyword(s):  
Structural Analysis ◽  
Binding Affinity ◽  
Receptor Binding ◽  
Conformational Changes ◽  
Spike Protein ◽  
Molecular Characteristics ◽  
Wild Type ◽  
Natural Mutation ◽  
The Stability ◽  
Different Strains

Abstract The emergence of some mutations in the SARS-CoV-2 receptor binding domain (RBD) can increase the spread and pathogenicity due to the conformational changes and increase the stability of Spike protein. Due to the formation of different strains of SARS-CoV-2 by mutations, and their catastrophic effect on public health, the study of the effect of mutations by scientists and researchers around the world is inevitable. According to available evidence, the S494P variant is observed in several SARS-CoV-2 strains from Michigan, USA. To investigate how the S494P natural mutation alters receptor binding affinity in RBD, we performed structural analysis of wild-type and mutant spike proteins using some bioinformatics and computational tools. The results show that S494P mutation increases the spike protein stability. Also, applying docking by HADDOCK displayed higher binding affinity to hACE2 for mutant spike than wild type possibly due to the increased β-strand and Turn secondary structures which increases surface accessibly surface area (SASA) and chance of interaction. The analysis of S494P as a critical RBD mutation may provide the continuing surveillance of spike mutations to aid in the development of COVID-19 drugs and vaccines.

scholarly journals In Silico Mutagenesis Based Remodeling of SARs-CoV-1 Peptide (ATLQAIAS) to Inhibit SARs-CoV-2: Structural-dynamics and Free Energy Calculations

2020 ◽  
Author(s):  
Abbas Khan ◽  
Shaheena Umbreen ◽  
Asma Hameed ◽  
Rida Fatima ◽  
Ujala Zahoor ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Affinity ◽  
In Silico ◽  
Therapeutic Potential ◽  
Decomposition Analysis ◽  
Free Energy Calculations ◽  
Energy Decomposition Analysis ◽  
Energy Calculation ◽  
Binding Affinities ◽  
The World

Abstract Background:The prolific spread of COVID-19 caused by a novel coronavirus (SARS-CoV-2) from its epicenter in Wuhan, China, to every nook and cranny of the world after December 2019, jeopardize the prevailing health system in the world and has raised serious concerns about human safety. To date efforts are continuing to design small molecule inhibitor, vaccines and many other therapeutic options are practiced but their final therapeutic potential is still to be tested. Using the old drug or vaccine or peptides could aid this process to avoid such long experimental procedure. Results:Hence, here we have repurposed a small peptide (ATLQAIAS) from the previous study which reported the inhibitory effects of this peptide. We used in silico mutagenesis approach to design more peptides from the native wild peptide, which revealed that substitutions (T2W, T2Y, L3R and A5W) could increase the binding affinity of the peptide towards the 3CLpro. Furthermore, using MD simulation and free energy calculation confirmed its dynamics stability and stronger binding affinities. Per-residues energy decomposition analysis revealed that the specified substitution significantly increased the binding affinity at residue level. Conclusion:Our wide-ranging analyses of binding affinities disclosed that our designed peptide owns the potential to hinder the SARS-CoV-2 and will reduce the progression of SARs-CoV-2-borne pneumonia. Our analysis strongly suggests the experimental and clinical validation of these peptides to curtail the recent corona outbreak.

Sign in / Sign up

Export Citation Format

Share Document