scholarly journals In silico evaluation of the interaction between ACE2 and SARS-CoV-2 Spike protein in a hyperglycemic environment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Giovanni Sartore ◽  
Davide Bassani ◽  
Eugenio Ragazzi ◽  
Pietro Traldi ◽  
Annunziata Lapolla ◽  
...  
Keyword(s):  
Computational Analysis ◽  
Computational Approach ◽  
Spike Protein ◽  
Crystallographic Structure ◽  
Receptor Binding Domain ◽  
Salt Bridges ◽  
X Ray ◽  
Aromatic Interactions ◽  
Multiple Alternative ◽  
Native Condition

AbstractThe worse outcome of COVID-19 in people with diabetes mellitus could be related to the non-enzymatic glycation of human ACE2, leading to a more susceptible interaction with virus Spike protein. We aimed to evaluate, through a computational approach, the interaction between human ACE2 receptor and SARS-CoV-2 Spike protein under different conditions of hyperglycemic environment. A computational analysis was performed, based on the X-ray crystallographic structure of the Spike Receptor-Binding Domain (RBD)-ACE2 system. The possible scenarios of lysine aminoacid residues on surface transformed by glycation were considered: (1) on ACE2 receptor; (2) on Spike protein; (3) on both ACE2 receptor and Spike protein. In comparison to the native condition, the number of polar bonds (comprising both hydrogen bonds and salt bridges) in the poses considered are 10, 6, 6, and 4 for the states ACE2/Spike both native, ACE2 native/Spike glycated, ACE2 glycated/Spike native, ACE2/Spike both glycated, respectively. The analysis highlighted also how the number of non-polar contacts (in this case, van der Waals and aromatic interactions) significantly decreases when the lysine aminoacid residues undergo glycation. Following non-enzymatic glycation, the number of interactions between human ACE2 receptor and SARS-CoV-2 Spike protein is decreased in comparison to the unmodified model. The reduced affinity of the Spike protein for ACE2 receptor in case of non-enzymatic glycation may shift the virus to multiple alternative entry routes.

scholarly journals SARS-CoV-2, an evolutionary perspective of interaction with human ACE2 reveals undiscovered amino acids necessary for complex stability

2020 ◽  
Author(s):  
Vinicio Armijos-Jaramillo ◽  
Justin Yeager ◽  
Claire Muslin ◽  
Yunierkis Perez-Castillo
Keyword(s):  
Receptor Binding ◽  
Evolutionary Dynamics ◽  
Hot Spot ◽  
Critical Role ◽  
Human Cells ◽  
Binding Domain ◽  
Host Cells ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Salt Bridges

AbstractThe emergence of SARS-CoV-2 has resulted in more than 200,000 infections and nearly 9,000 deaths globally so far. This novel virus is thought to have originated from an animal reservoir, and acquired the ability to infect human cells using the SARS-CoV cell receptor hACE2. In the wake of a global pandemic it is essential to improve our understanding of the evolutionary dynamics surrounding the origin and spread of a novel infectious disease. One way theory predicts selection pressures should shape viral evolution is to enhance binding with host cells. We first assessed evolutionary dynamics in select betacoronavirus spike protein genes to predict where these genomic regions are under directional or purifying selection between divergent viral lineages at various scales of relatedness. With this analysis, we determine a region inside the receptor-binding domain with putative sites under positive selection interspersed among highly conserved sites, which are implicated in structural stability of the viral spike protein and its union with human receptor hACE2. Next, to gain further insights into factors associated with coronaviruses recognition of the human host receptor, we performed modeling studies of five different coronaviruses and their potential binding to hACE2. Modeling results indicate that interfering with the salt bridges at hot spot 353 could be an effective strategy for inhibiting binding, and hence for the prevention of coronavirus infections. We also propose that a glycine residue at the receptor binding domain of the spike glycoprotein can have a critical role in permitting bat variants of the coronaviruses to infect human cells.

scholarly journals Computational approach to design of aptamers to the receptor binding domain of SARS-CoV-2

2021 ◽  
pp. 66-67
Author(s):  
P.V. Artyushenko ◽  
◽  
V.A. Mironov ◽  
D.I. Morozov ◽  
I.A. Shchugoreva ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Molecular Dynamic ◽  
Quantum Chemical Calculations ◽  
In Silico ◽  
Quantum Chemical ◽  
Computational Approach ◽  
Receptor Binding Domain ◽  
Dynamic Simulations ◽  
X Ray ◽  
X Ray Scattering

The aim of the research. In this work, in silico selection of DNA-aptamers to the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein was performed using molecular modeling methods. Material and methods. A new computational approach to aptamer in silico selection is based on a cycle of simulations, including the stages of molecular modeling, molecular docking, molecular dynamic simulations, and quantum chemical calculations. To verify the obtained calculated results flow cytometry, fluorescence polarization, and small-angle X-ray scattering methods were applied. Results. An initial library consisted of 256 16-mer oligonucleotides was modeled. Based on molecular docking results, the only one aptamer (Apt16) was selected from the library as a starting aptamer to the RBD protein. For Apt16/RBD complex, molecular dynamic and quantum chemical calculations revealed the pairs of nucleotides and amino acids whose contribution to the binding between aptamer and RBD is the largest. Taking into account these data, Apt16 was subjected to the structure modifi cations in order to increase the binding with the RBD. Th us, a new aptamer Apt25 was designed. Th e procedure of 1) aptamer structure modeling/modifi cation, 2) molecular docking, 3) molecular dynamic simulations, 4) quantum chemical calculations was performed several times. As a result, four aptamers (Apt16, Apt25, Apt27, Apt31) to the RBD were designed in silico without any preliminary experimental data. Binding of the each modeled aptamer to the RBD was studied in terms of interactions between residues in protein and nucleotides in the aptamers. Based on the simulation results, the strongest binding with the RBD was predicted for two Apt27 and Apt31aptamers. The calculated results are in good agreement with experimental data obtained by flow cytometry, fluorescence polarization, and small-angle X-ray scattering methods. Conclusion. Th e proposed computational approach to selection and refi nement of aptamers is universal and can be used for wide range of molecular ligands and targets

scholarly journals A model for pH coupling of the SARS-CoV-2 spike protein open/closed equilibrium

2020 ◽  
Author(s):  
Jim Warwicker
Keyword(s):  
Cell Surface ◽  
Aspartic Acid ◽  
Receptor Binding ◽  
Ph Dependence ◽  
Salt Bridge ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Salt Bridges ◽  
Heat Map ◽  
Human Coronaviruses

AbstractSARS-CoV-2, causative agent of the COVID-19 pandemic, is thought to release its RNA genome at either the cell surface or within endosomes, the balance being dependent on spike protein stability, and the complement of receptors, co-receptors and proteases. To investigate possible mediators of pH-dependence, pKa calculations have been made on a set of structures for spike protein ectodomain and fragments from SARS-CoV-2 and other coronaviruses. Dominating a heat map of the aggregated predictions, 3 histidine residues in S2 are consistently predicted as destabilising in pre-fusion (all 3) and post-fusion (2 of 3) structures. Other predicted features include the more moderate energetics of surface salt-bridge interactions, and sidechain-mainchain interactions. Two aspartic acid residues in partially buried salt-bridges have pKas that are calculated to be elevated and destabilising. Notably, the degree of destabilisation is predicted to vary between open and closed receptor binding domain conformations. It is therefore suggested that these groups contribute to a pH-dependence of the open/closed equilibrium. These observations are discussed in the context of SARS-CoV-2 infection, mutagenesis studies, and other human coronaviruses.

scholarly journals Molecular basis for SARS-CoV-2 spike affinity for human ACE2 receptor

2020 ◽  
Author(s):  
Julián M. Delgado ◽  
Nalvi Duro ◽  
David M. Rogers ◽  
Alexandre Tkatchenko ◽  
Sagar A. Pandit ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Basis ◽  
Free Energy Calculations ◽  
Spike Protein ◽  
Salt Bridges ◽  
Recognition Mechanism ◽  
X Ray ◽  
Receptor Recognition ◽  
Structural Fluctuations ◽  
Dynamics Simulations

AbstractSevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused substantially more infections, deaths, and economic disruptions than the 2002-2003 SARS-CoV. The key to understanding SARS-CoV-2’s higher infectivity may lie in its host receptor recognition mechanism. This is because experiments show that the human ACE2 protein, which serves as the primary receptor for both CoVs, binds to CoV-2’s spike protein 5-20 fold stronger than SARS-CoV’s spike protein. The molecular basis for this difference in binding affinity, however, remains unexplained and, in fact, a comparison of X-ray structures leads to an opposite proposition. To gain insight, we use all-atom molecular dynamics simulations. Free energy calculations indicate that CoV-2’s higher affinity is due primarily to differences in specific spike residues that are local to the spike-ACE2 interface, although there are allosteric effects in binding. Comparative analysis of equilibrium simulations reveals that while both CoV and CoV-2 spike-ACE2 complexes have similar interfacial topologies, CoV-2’s spike protein engages in greater numbers, combinatorics and probabilities of hydrogen bonds and salt bridges with ACE2. We attribute CoV-2’s higher affinity to these differences in polar contacts, and these findings also highlight the importance of thermal structural fluctuations in spike-ACE2 complexation. We anticipate that these findings will also inform the design of spike-ACE2 peptide blockers that, like in the cases of HIV and Influenza, can serve as antivirals.

scholarly journals Computational analysis on the ACE2-derived peptides for neutralizing the ACE2 binding to the spike protein of SARS-CoV-2

2020 ◽  
Author(s):  
Cecylia S. Lupala ◽  
Vikash Kumar ◽  
Xuanxuan Li ◽  
Xiao-dong Su ◽  
Haiguang Liu
Keyword(s):  
Molecular Dynamics ◽  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Computational Analysis ◽  
Spike Protein ◽  
Short Peptides ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Dynamics Simulations

ABSTRACTThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19, is spreading globally and has infected more than 3 million people. It has been discovered that SARS-CoV-2 initiates the entry into cells by binding to human angiotensin-converting enzyme 2 (hACE2) through the receptor binding domain (RBD) of its spike glycoprotein. Hence, drugs that can interfere the SARS-CoV-2-RBD binding to hACE2 potentially can inhibit SARS-CoV-2 from entering human cells. Here, based on the N-terminal helix α1 of human ACE2, we designed nine short peptides that have potential to inhibit SARS-CoV-2 binding. Molecular dynamics simulations of peptides in the their free and SARS-CoV-2 RBD-bound forms allow us to identify fragments that are stable in water and have strong binding affinity to the SARS-CoV-2 spike proteins. The important interactions between peptides and RBD are highlighted to provide guidance for the design of peptidomimetics against the SARS-CoV-2.

scholarly journals Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape

Science ◽  
2021 ◽  
Vol 371 (6530) ◽  
pp. eabe6230 ◽  
Author(s):  
Paul-Albert Koenig ◽  
Hrishikesh Das ◽  
Hejun Liu ◽  
Beate M. Kümmerer ◽  
Florian N. Gohr ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Receptor Binding ◽  
Conformational Changes ◽  
Passive Immunization ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
X Ray ◽  
X Ray Crystallography ◽  
Cryo Electron Microscopy ◽  
Escape Mutants

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread, with devastating consequences. For passive immunization efforts, nanobodies have size and cost advantages over conventional antibodies. In this study, we generated four neutralizing nanobodies that target the receptor binding domain of the SARS-CoV-2 spike protein. We used x-ray crystallography and cryo–electron microscopy to define two distinct binding epitopes. On the basis of these structures, we engineered multivalent nanobodies with more than 100 times the neutralizing activity of monovalent nanobodies. Biparatopic nanobody fusions suppressed the emergence of escape mutants. Several nanobody constructs neutralized through receptor binding competition, whereas other monovalent and biparatopic nanobodies triggered aberrant activation of the spike fusion machinery. These premature conformational changes in the spike protein forestalled productive fusion and rendered the virions noninfectious.

The X-ray Crystallographic Structure of Human EAT2 (SH2D1B)

2016 ◽  
Vol 23 (10) ◽  
pp. 862-866 ◽  
Author(s):  
Mohammed Taha ◽  
Eric Nezerwa ◽  
Hyun-Joo Nam
Keyword(s):  
Crystallographic Structure ◽  
X Ray
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