The Omicron Variant Increases the Interactions of SARS-CoV-2 Spike Glycoprotein with ACE2

The Omicron variant (B.1.1.529) comprises 30 mutations on the spike glycoprotein (S), 15 of which are located on its receptor-binding domain (RBD_Omicron). RBD interacts with the peptidase domain (PD) of angiotensin-converting enzyme 2 (ACE2) receptors and plays a critical role in the host cell entry of the virus. We performed all-atom simulations of the RBD_Omicron-PD in the presence of explicit water and ions. Simulations showed a considerably more extensive interactions network between RBD_Omicron and PD compared to RBD_WT, comprising a 250%, 10% and -25% change in the total number of salt bridges, hydrophobic interactions, hydrogen bonds at the S-ACE2 interface, respectively. Using the conformations sampled in each our MD trajectories, binding energies of two sets of RBD_WT-PD and four sets of RBD_Omicron-PD simulations were calculated via the Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) method, estimating ~44% stronger binding energy for RBD_Omicron compared to RBD_WT. Our results suggest that an increase in the number of salt bridges in the S-ACE2 interface result in a higher binding strength of RBD to PD, which may result in a higher efficiency of the SARS-CoV-2 virus to infect host cells. Furthermore, RBD_Omicron exhibits a more dispersed interaction network on both sides of the RBD-PD interaction surface compared to WT.

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

10.1101/2020.03.21.001933 ◽

2020 ◽

Cited By ~ 4

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.

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Critical Negatively Charged Residues Are Important for the Activity of SARS-CoV-1 and SARS-CoV-2 Fusion Peptides

10.1101/2021.11.03.467161 ◽

2021 ◽

Author(s):

Alex L. Lai ◽

Jack H. Freed

Keyword(s):

Critical Role ◽

Binding Energies ◽

Host Cells ◽

Topological Model ◽

Pseudotyped Virus ◽

Fusion Peptides ◽

Human Pathogens ◽

Charged Residues ◽

The Difference

AbstractCoronaviruses are a major infectious disease threat, and include the human pathogens of zoonotic origin SARS-CoV (“SARS-1”), SARS-CoV-2 (“SARS-2”) and MERS-CoV (“MERS”). Entry of coronaviruses into host cells is mediated by the viral spike (S) protein. Previously, we identified that the domain immediately downstream of the S2’ cleavage site is the bona fide FP (amino acids 798-835) for SARS-1 using ESR spectroscopy technology. We also found that the SARS-1 FP induces membrane ordering in a Ca2+ dependent fashion. In this study, we want to know which residues are involved in this Ca2+ binding, to build a topological model and to understand the role of the Ca2+. We performed a systematic mutation study on the negatively charged residues on the SARS-1 FP. While all six negatively charged residues contributes to the membrane ordering activity of the FP to some extent, D812 is the most important residue. We provided a topological model of how the FP binds Ca2+ ions: both FP1 and FP2 bind one Ca2+ ion, and there are two binding sites in FP1 and three in FP2. We also found that the corresponding residue D830 in the SARS-2 FP plays a similar critical role. ITC experiments show that the binding energies between the FP and Ca2+ as well as between the FP and membranes also decreases for all mutants. The binding of Ca2+, the folding of FP and the ordering activity correlated very well across the mutants, suggesting that the function of the Ca2+ is to help to folding of FP in membranes to enhance its activity. Using a novel pseudotyped virus particle (PP)-liposome methodology, we monitored the membrane ordering induced by the FPs in the whole S proteins in its trimer form in real time. We found that the SARS-1 and SARS-2 PPs also induce membrane ordering as the separate FPs do, and the mutations of the negatively charged residues also greatly reduce the membrane ordering activity. However, the difference in kinetic between the PP and FP indicates a possible role of FP trimerization. This finding could lead to therapeutic solutions that either target the FP-calcium interaction or block the Ca2+ channel to combat the ongoing COVID-19 pandemic.

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Screening, simulation, and optimization design of small molecule inhibitors of the SARS-CoV-2 spike glycoprotein

PLoS ONE ◽

10.1371/journal.pone.0245975 ◽

2021 ◽

Vol 16 (1) ◽

pp. e0245975

Author(s):

Chuancai Sun ◽

Jian Zhang ◽

Jiao Wei ◽

Xiaoli Zheng ◽

Xianyang Zhao ◽

...

Keyword(s):

Small Molecule ◽

Conformational Changes ◽

Binding Sites ◽

Optimization Design ◽

Binding Energies ◽

Host Cells ◽

Spike Glycoprotein ◽

S Protein ◽

Simulation And Optimization ◽

Interaction Sites

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak is a public health emergency of international concern. The spike glycoprotein (S protein) of SARS-CoV-2 is a key target of antiviral drugs. Focusing on the existing S protein structure, molecular docking was used in this study to calculate the binding energy and interaction sites between 14 antiviral molecules with different structures and the SARS-CoV-2 S protein, and the potential drug candidates targeting the SARS-CoV-2 S protein were analyzed. Tizoxanide, dolutegravir, bictegravir, and arbidol were found to have high binding energies, and they effectively bind key sites of the S1 and S2 subunits, inhibiting the virus by causing conformational changes in S1 and S2 during the fusion of the S protein with host cells. Based on the interactions among the drug molecules, the S protein and the amino acid environment around the binding sites, rational structure-based optimization was performed using the molecular connection method and bioisosterism strategy to obtain Ti-2, BD-2, and Ar-3, which have much stronger binding ability to the S protein than the original molecules. This study provides valuable clues for identifying S protein inhibitor binding sites and the mechanism of the anti-SARS-CoV-2 effect as well as useful inspiration and help for the discovery and optimization of small molecule S protein inhibitors.

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Virtual Screening of Plant-Derived Compounds Against SARS-CoV-2 Viral Proteins Using Computational Tools

10.26434/chemrxiv.13118117 ◽

2020 ◽

Author(s):

Maria Antonela Zigolo ◽

Matías Rivero Goytia ◽

Hugo Ramiro Poma ◽

Verónica Rajal ◽

Veronica Patricia Irazusta

Keyword(s):

Hydrophobic Interactions ◽

Viral Proteins ◽

Natural Compounds ◽

Docking Studies ◽

Binding Energies ◽

Host Cells ◽

Computational Tools ◽

S Protein ◽

Synthetic Drugs ◽

Main Protease

The new SARS-CoV-2, responsible for the COVID-19 pandemic, has been threatening public health worldwide for half a year. The aim of this work was to evaluate compounds of natural origin, mainly from medicinal plants, as potential SARS-CoV-2 inhibitors through docking studies. The viral spike (S) glycoprotein and the main protease Mpro, involved in the recognition of virus by host cells and in viral replication, respectively, were the main molecular targets in this study. The best energy binding values for S protein were, in kcal/mol: -19.22 for glycyrrhizin, -17.84 for gitoxin, -12.05 for dicumarol, -10.75 for diosgenin, and -8.12 for delphinidin. For Mpro were, in kcal/mol: -9.36 for spirostan, -8.75 for N-(3-acetylglycyrrhetinoyl)-2-amino-propanol, -8.41 for α-amyrin, -8.35 for oleanane, -8.11 for taraxasterol, and -8.03 for glycyrrhetinic acid. In addition, the synthetic drugs umifenovir, chloroquine, and hydroxychloroquine were used as controls for S protein, while atazanavir and nelfinavir were used for Mpro. Key hydrogen bonds and hydrophobic interactions between natural compounds and the respective viral proteins were identified, allowing us to explain the great affinity obtained in those compounds with the lowest binding energies. These results suggest that these natural compounds could potentially be useful as drugs to be experimentally evaluated against COVID-19.

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Cross-species recognition of SARS-CoV-2 to bat ACE2

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2020216118 ◽

2020 ◽

Vol 118 (1) ◽

pp. e2020216118

Author(s):

Kefang Liu ◽

Shuguang Tan ◽

Sheng Niu ◽

Jia Wang ◽

Lili Wu ◽

...

Keyword(s):

Binding Capacity ◽

Species Recognition ◽

Interaction Network ◽

Binding Mode ◽

Host Cells ◽

Structural Basis ◽

Receptor Binding Domain ◽

Angiotensin Converting Enzyme 2 ◽

Protein Receptor ◽

Human Receptor

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a major threat to global health. Although varied SARS-CoV-2–related coronaviruses have been isolated from bats and SARS-CoV-2 may infect bat, the structural basis for SARS-CoV-2 to utilize the human receptor counterpart bat angiotensin-converting enzyme 2 (bACE2) for virus infection remains less understood. Here, we report that the SARS-CoV-2 spike protein receptor binding domain (RBD) could bind to bACE2 fromRhinolophus macrotis(bACE2-Rm) with substantially lower affinity compared with that to the human ACE2 (hACE2), and its infectivity to host cells expressing bACE2-Rm was confirmed with pseudotyped SARS-CoV-2 virus and SARS-CoV-2 wild virus. The structure of the SARS-CoV-2 RBD with the bACE2-Rm complex was determined, revealing a binding mode similar to that of hACE2. The analysis of binding details between SARS-CoV-2 RBD and bACE2-Rm revealed that the interacting network involving Y41 and E42 of bACE2-Rm showed substantial differences with that to hACE2. Bats have extensive species diversity and the residues for RBD binding in bACE2 receptor varied substantially among different bat species. Notably, the Y41H mutant, which exists in many bats, attenuates the binding capacity of bACE2-Rm, indicating the central roles of Y41 in the interaction network. These findings would benefit our understanding of the potential infection of SARS-CoV-2 in varied species of bats.

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Screening of World Approved Drugs against Highly Dynamical Spike Glycoprotein SARS-CoV-2 using CaverDock and Machine Learning

10.26434/chemrxiv.13168883.v2 ◽

2020 ◽

Author(s):

Gaspar Pinto ◽

Ondrej Vavra ◽

Sérgio M. Marques ◽

Jiri Filipovic ◽

David Bednar ◽

...

Keyword(s):

Tertiary Structure ◽

Binding Energies ◽

Rapid Screening ◽

Spike Glycoprotein ◽

Multivariate Statistical ◽

Angiotensin Converting Enzyme 2 ◽

Full Dataset ◽

Zinc Database ◽

Approved Drugs ◽

Dynamics Simulations

The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes pathological pulmonary symptoms. Most efforts to develop vaccines and drugs against this virus target the spike glycoprotein, particularly its S1 subunit, which is recognised by angiotensin-converting enzyme 2. Here we use the in-house developed tool CaverDock to perform virtual screening against spike glycoprotein using a cryogenic electron microscopy structure (PDB-ID: 6VXX) and the representative structures of five most populated clusters from a previously published molecular dynamics simulations. The dataset of ligands was obtained from the ZINC database and consists of drugs approved for clinical use worldwide. Trajectories for the passage of individual drugs through the tunnel of the spike glycoprotein homotrimer, their binding energies within the tunnel, and the duration of their contacts with the trimer’s three subunits were computed for the full dataset. Multivariate statistical methods were then used to establish structure-activity relationships and select top candidate molecules. This new protocol for rapid screening of globally approved drugs (4359 ligands) in a multi-state protein structure (6 states) required a total of 26,148 calculations and showed high robustness. The protocol is universal and can be applied to any target protein with an experimental tertiary structure containing protein tunnels or channels. The protocol will be implemented in the next version of CaverWeb (<a href="https://loschmidt.chemi.muni.cz/caverweb/">https://loschmidt.chemi.muni.cz/caverweb/</a>) to make it accessible to the wider scientific community

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Andrographolide binds to spike glycoprotein and RNA-dependent RNA polymerase (NSP12) of SARS-CoV-2 by in silico approach: a probable molecule in the development of anti-coronaviral drug

Journal of Genetic Engineering and Biotechnology ◽

10.1186/s43141-021-00201-7 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Lokanathan Srikanth ◽

Potukuchi Venkata Gurunadha Krishna Sarma

Keyword(s):

Rna Polymerase ◽

In Silico ◽

Host Cells ◽

Spike Glycoprotein ◽

Leaf Extracts ◽

Rna Dependent Rna Polymerase ◽

Angiotensin Converting Enzyme 2 ◽

Naturally Occurring ◽

The Family ◽

Inhibitory Molecules

AbstractThe SARS-CoV-2 belongs to Coronaviridae family infects host cells by the interaction of its spike glycoprotein and angiotensin-converting enzyme 2 (ACE 2) of host cells. Upon entry, the virus uses its RNA dependent RNA polymerase (NSP12) for transcribing its genome to survive in the cell and spread its infection. The protein sequences of receptor-binding domain (RBD) of spike glycoprotein, and NSP12 exhibits high homology in the family of Coronoviridae and are ideal candidates for the development of anti-coronaviral drugs. In the quest to identify inhibitory molecules against these proteins, we searched several molecules that are present in naturally occurring medicinal plants database. Andrographolide which is largely present in the leaf extracts of Andrographis paniculata (AP) and is known to exhibit antiviral, antibacterial, and stabilizes Th1/Th2/Th17 responses; taking this clue, we used in silico approaches to see the binding of andrographolide to RBD and NSP12 molecules. Our docking results showed very strong affinity of andrographolide to RBD and NSP12 of the SARS-CoV-2 virus with dock scores of −10.3460 for RBD and −10.7313 for NSP12 indicating andrographolide acts as an inhibitor of RBD and NSP12. These unique properties of andrographolide, AP extract, can be tested as anti-coronaviral drug.

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Screening of World Approved Drugs against Highly Dynamical Spike Glycoprotein SARS-CoV-2 using CaverDock and Machine Learning

10.26434/chemrxiv.13168883 ◽

2020 ◽

Author(s):

Gaspar Pinto ◽

Ondrej Vavra ◽

Sérgio M. Marques ◽

Jiri Filipovic ◽

David Bednar ◽

...

Keyword(s):

Tertiary Structure ◽

Binding Energies ◽

Rapid Screening ◽

Spike Glycoprotein ◽

Multivariate Statistical ◽

Angiotensin Converting Enzyme 2 ◽

Full Dataset ◽

Zinc Database ◽

Approved Drugs ◽

Dynamics Simulations

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Hydrogen Bond Networks and Hydrophobic Effects in the Amyloid β30–35 Chain in Water: A Molecular Dynamics Study

10.1101/090092 ◽

2016 ◽

Author(s):

KwangHyok Jong ◽

Luca Grisanti ◽

Ali Hassanali

Keyword(s):

Hydrogen Bond ◽

Electrostatic Interactions ◽

Hydrophobic Interactions ◽

Critical Role ◽

Protein A ◽

Intrinsically Disordered Protein ◽

Salt Bridges ◽

Intrinsically Disordered ◽

Hydrogen Bond Networks ◽

Squeeze Out

AbstractWe study the conformational landscape of the C-terminal fragment of the Amyloid protein Aβ30–35 in water using well-tempered metadynamics simulations and find that it resembles an intrinsically disordered protein. The conformational fluctuations of the protein are facilitated by a collective reorganization of both protein and water hydrogen bond networks, combined with electrostatic interactions between termini as well as hydrophobic interactions of the side chains. The stabilization of hydrophobic interactions in one of the conformers involves a collective collapse of the sidechains along with a squeeze out of water sandwiched in between. The charged N and C termini play a critical role in stabilizing different types of protein conformations including those involving contact ion salt-bridges as well as solvent mediated interactions of the termini and amide backbone. We examine this by probing the distribution of directed water wires forming the hydrogen bond network enveloping the polypeptide. Water wires and their fluctuations form an integral part of structural signature of the protein conformation.

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Targeting SARS-CoV-2 Spike Protein of COVID-19 with Naturally Occurring Phytochemicals: An in Silco Study for Drug Development

10.26434/chemrxiv.12094203.v1 ◽

2020 ◽

Cited By ~ 6

Author(s):

Jitendra Subhash Rane ◽

Aroni Chatterjee ◽

Abhijeet Kumar ◽

Shashikant Ray

Keyword(s):

Receptor Binding ◽

Docking Study ◽

Binding Energies ◽

Host Cells ◽

Spike Protein ◽

Molecular Docking Study ◽

Angiotensin Converting Enzyme 2 ◽

Naturally Occurring

Spike glycoprotein found on the surface of SARS-CoV-2 (SARS-CoV-2S) is a class I fusion protein which helps the virus in its initial attachment with human Angiotensin converting enzyme 2 (ACE2) receptor and its consecutive fusion with the host cells. The attachment is mediated by the S1 subunit of the protein via its receptor binding domain. Upon binding with the receptor the protein changes its conformation from a pre-fusion to a post-fusion form. The membrane fusion and internalization of the virus is brought about by the S2 domain of the spike protein. From ancient times people have relied on naturally occurring substances like phytochemicals to fight against diseases and infection. Among these phytochemicals, flavonoids and non-flavonoids have been found to be the active source of different anti-microbial agents. Recently, studies have shown that these phytochemicals have essential anti-viral activities. We performed a molecular docking study using 10 potential naturally occurring flavonoids/non-flavonoids against the SARS-CoV-2 spike protein and compared their affinity with the FDA approved drug hydroxychloroquine (HCQ). Interestingly, the docking analysis suggested that C-terminal of S1 domain and S2 domain of the spike protein are important for binding with these compounds. Kamferol, curcumin, pterostilbene, and HCQ interact with the C-terminal of S1 domain with binding energies of -7.4, -7.1, -6.7 and -5.6 Kcal/mol, respectively. Fisetin, quercetin, isorhamnetin, genistein, luteolin, resveratrol and apigenin on the other hand, interact with the S2 domain of spike protein with the binding energies of -8.5, -8.5, -8.3, -8.2, -8.2, -7.9, -7.7 Kcal/mol, respectively. Our study suggested that, these flavonoid and non-flavonoid moieties have significantly high binding affinity for the two main important domains of the spike protein which is responsible for the attachment and internalization of the virus in the host cell and their binding affinities are much higher compared to that of HCQ. In addition, ADME (absorption, distribution, metabolism and excretion) analysis also suggested that these compounds consist of drug likeness property which may help for further explore as anti-SARS-CoV-2 agents. Further, in vitro and in vivo study of these compounds will provide a clear path for the development of novel compounds that would most likely prevent the receptor binding or internalization of the SARS-CoV-2 spike protein and therefore could be used as drugs for COVID-19 therapy.

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