scholarly journals Enhanced receptor binding of SARS-CoV-2 through networks of hydrogen-bonding and hydrophobic interactions

2020 ◽  
Vol 117 (25) ◽  
pp. 13967-13974 ◽  
Author(s):  
Yingjie Wang ◽  
Meiyi Liu ◽  
Jiali Gao
Keyword(s):  
Hydrogen Bonding ◽  
Receptor Binding ◽  
Protein Interactions ◽  
Hydrophobic Interactions ◽  
Contact Region ◽  
Complex Model ◽  
Receptor Protein ◽  
Hydrophobic Region ◽  
Hydrophobic Contact ◽  
Binding Interface

Molecular dynamics and free energy simulations have been carried out to elucidate the structural origin of differential protein–protein interactions between the common receptor protein angiotensin converting enzyme 2 (ACE2) and the receptor binding domains of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [A. E. Gorbalenyaet al.,Nat. Microbiol.5, 536–544 (2020)] that causes coronavirus disease 2019 (COVID-19) [P. Zhouet al.,Nature579, 270–273 (2020)] and the SARS coronavirus in the 2002–2003 (SARS-CoV) [T. Kuikenet al., Lancet 362, 263–270 (2003)] outbreak. Analysis of the dynamic trajectories reveals that the binding interface consists of a primarily hydrophobic region and a delicate hydrogen-bonding network in the 2019 novel coronavirus. A key mutation from a hydrophobic residue in the SARS-CoV sequence to Lys417 in SARS-CoV-2 creates a salt bridge across the central hydrophobic contact region, which along with polar residue mutations results in greater electrostatic complementarity than that of the SARS-CoV complex. Furthermore, both electrostatic effects and enhanced hydrophobic packing due to removal of four out of five proline residues in a short 12-residue loop lead to conformation shift toward a more tilted binding groove in the complex in comparison with the SARS-CoV complex. On the other hand, hydrophobic contacts in the complex of the SARS-CoV–neutralizing antibody 80R are disrupted in the SARS-CoV-2 homology complex model, which is attributed to failure of recognition of SARS-CoV-2 by 80R.

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 Elucidating the differences in the molecular mechanism of receptor binding between 2019-nCoV and the SARS-CoV viruses using computational tools

2020 ◽  
Author(s):  
Hien T. T. Lai ◽  
Ly H. Nguyen ◽  
Agata Kranjc ◽  
Toan T. Nguyen ◽  
Duc Nguyen-Manh
Keyword(s):  
Receptor Binding ◽  
Elderly Population ◽  
Hydrophobic Interactions ◽  
Viral Disease ◽  
World Health ◽  
Pharmacological Intervention ◽  
Computational Tools ◽  
Viral Genomes ◽  
Binding Interface ◽  
Health Organization

AbstractThe outbreak of the 2019-nCoV coronavirus causing severe acute respiratory syndrome which can be fatal, especially in elderly population, has been declared a pandemic by the World Health Organization. Many biotechnology laboratories are rushing to develop therapeutic antibodies and antiviral drugs for treatment of this viral disease. The viral CoV spike (S) glycoprotein is one of the main targets for pharmacological intervention. Its receptor-binding domain (RBD) interacts with the human ACE2 receptor ensuring the entry of the viral genomes into the host cell. In this work, we report on the differences in the binding of the RBD of the previous coronavirus SARS-CoV and of the newer 2019-nCoV coronavirus to the human ACE2 receptor using atomistic molecular dynamics techniques. Our results show major mutations in the 2019-nCoV RBD with respect to the SARS-CoV RBD occurring at the interface of RBD-ACE2 complex. These mutations make the 2019-nCoV RBD protein backbone much more flexible, hydrophobic interactions are reduced and additional polar/charged residues appear at the interface. We observe that higher flexibility of the 2019-nCoV RBD with respect to the SARS-CoV RBD leads to a bigger binding interface between the 2019-nCoV RBD and ACE2 and to about 20% more contacts between them in comparison with SARS-CoV. Taken together, the 2019-nCoV RBD shows more stable binding interface and higher binding affinity for the ACE2 receptor. The mutations not only stabilize the binding interface, they also lead to overall more stable 2019-nCoV RBD protein structure, even far from the binding interface. Our results on the molecular differences in the binding between the two viruses can provide important inputs for development of appropriate antiviral treatments of the new viruses, addressing the necessity of ongoing pandemics.

scholarly journals Computer Simulations of the interaction between SARS-CoV-2 spike glycoprotein and different surfaces

2020 ◽  
Author(s):  
David C. Malaspina ◽  
Jordi Faraudo
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bonding ◽  
Receptor Binding ◽  
Hydrophobic Interactions ◽  
Prominent Feature ◽  
High Hydrogen ◽  
Binding Domains ◽  
Dynamics Simulations ◽  
Initial Adsorption ◽  
Binding Subunit

A prominent feature of coronaviruses is the presence of a large glycoprotein spike protruding from a lipidic membrane. This glycoprotein spike determines the interaction of coronaviruses with the environment and the host. In this paper, we perform all atomic Molecular Dynamics simulations of the interaction between the SARS-CoV-2 trimeric glycoprotein spike and surfaces of materials. We considered a material with high hydrogen bonding capacity (cellulose) and a material capable of strong hydrophobic interactions (graphite). Initially, the spike adsorbs to both surfaces through essentially the same residues belonging to the receptor binding subunit of its three monomers. Adsorption onto cellulose stabilizes in this configuration, with the help of a large number of hydrogen bonds developed between cellulose and the three receptor binding domains (RBD) of the glycoprotein spike. In the case of adsorption onto graphite, the initial adsorption configuration is not stable and the surface induces a substantial deformation of the glycoprotein spike with a large number of adsorbed residues not pertaining to the binding subunits of the spike monomers.

scholarly journals Binding mechanism of SARS-CoV-2 spike protein with human ACE2 receptor

2020 ◽  
Author(s):  
Rajendra P Koirala ◽  
Bidhya Thapa ◽  
Shyam P Khanal ◽  
Jhulan Powrel ◽  
Rajendra P Adhikari ◽  
...  
Keyword(s):  
Free Energy ◽  
Contact Surface ◽  
Hydrophobic Interactions ◽  
Binding Free Energy ◽  
Umbrella Sampling ◽  
Spike Protein ◽  
Receptor Protein ◽  
Virus Protein ◽  
Binding Mechanism ◽  
Binding Interface

Abstract SARS-CoV-2 virus interacts via C-terminal domain of spike protein to human cell receptor protein hACE2. Amino acid residues residing at the interface play vital role in binding of SARS-CoV-2 CTD to hACE2. The detailed atomic level inves- tigation of interactions at binding interface of SARS-CoV-2 CTD/hACE2 provides indispensable information on better understanding of location for drug target. In the present work, we have studied the dynamical behaviour of the complex by ana- lyzing the molecular dynamics (MD) trajectories. The major interacting residues of SARS-CoV-2 CTD and hACE2 have been identified by analyzing the non-bonded interactions such as hydrogen bondings, salt bridges, hydrophobic interactions, van der Waals interactions etc. Umbrella sampling method has been used to estimate the binding free energy for in-depth understanding of binding mechanism between virus protein and host receptor. The binding free energy difference, key residues at the interface, important atomic interactions and contact surface areas have been compared with the molecular complex of SARS-CoV and hACE2. Relatively larger contact surface area, more non-bonded interactions as well as greater binding free energy provide the evidence for favorable binding of SARS-CoV-2 with hACE2 receptor than SARS-CoV.

scholarly journals Identifying key determinants and dynamics of SARS-CoV-2/ACE2 tight interaction

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257905
Author(s):  
Van A. Ngo ◽  
Ramesh K. Jha
Keyword(s):  
Receptor Binding ◽  
Dissociation Rate ◽  
Receptor Protein ◽  
Terminal Part ◽  
Angiotensin Converting Enzyme 2 ◽  
Binding Interface ◽  
Global Pandemic ◽  
Key Residues ◽  
Insight Into ◽  
Human Receptor

SARS-CoV-2 virus, the causative agent of Covid-19, has fired up a global pandemic. The virus interacts with the human receptor angiotensin-converting enzyme 2 (ACE2) for an invasion via receptor binding domain (RBD) on its spike protein. To provide a deeper understanding of this interaction, we performed microsecond simulations of the RBD-ACE2 complex for SARS-CoV-2 and compared it with the closely related SARS-CoV discovered in 2003. We show residues in the RBD of SARS-CoV-2 that were mutated from SARS-CoV, collectively help make the RBD anchor much stronger to the N-terminal part of ACE2 than the corresponding residues on RBD of SARS-CoV. This would result in a reduced dissociation rate of SARS-CoV-2 from human receptor protein compared to SARS-CoV. The phenomenon was consistently observed in simulations beyond 500 ns and was reproducible across different force fields. Altogether, our study adds more insight into the critical dynamics of the key residues at the virus spike and human receptor binding interface and potentially aids the development of diagnostics and therapeutics to combat the pandemic efficiently.

scholarly journals Measuring ligand-dependent and ligand-independent interactions between nuclear receptors and associated proteins using Bioluminescence Resonance Energy Transfer (BRET2)

2006 ◽  
Vol 4 (1) ◽  
pp. nrs.04021 ◽  
Author(s):  
Kristen L. Koterba ◽  
Brian G. Rowan
Keyword(s):  
Energy Transfer ◽  
Protein Interactions ◽  
Fusion Proteins ◽  
Fluorescent Protein ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Renilla Luciferase ◽  
Receptor Protein ◽  
Protein Protein Interactions

Bioluminescent resonance energy transfer (BRET2) is a recently developed technology for the measurement of protein-protein interactions in a live, cell-based system. BRET2 is characterized by the efficient transfer of excited energy between a bioluminescent donor molecule (Renilla luciferase) and a fluorescent acceptor molecule (a mutant of Green Fluorescent Protein (GFP2)). The BRET2 assay offers advantages over fluorescence resonance energy transfer (FRET) because it does not require an external light source thereby eliminating problems of photobleaching and autoflourescence. The absence of contamination by light results in low background that permits detection of very small changes in the BRET2 signal. BRET2 is dependent on the orientation and distance between two fusion proteins and therefore requires extensive preliminary standardization experiments to conclude a positive BRET2 signal independent of variations in protein titrations and arrangement in tertiary structures. Estrogen receptor (ER) signaling is modulated by steroid receptor coactivator 1 (SRC-1). To establish BRET2 in a ligand inducible system we used SRC-1 as the donor moiety and ER as the acceptor moiety. Expression and functionality of the fusion proteins were assessed by transient transfection in HEK-293 cells followed by Western blot analysis and measurement of ER-dependent reporter gene activity. These preliminary determinations are required prior to measuring nuclear receptor protein-protein interactions by BRET2. This article describes in detail the BRET2 methodology for measuring interaction between full-length ER and coregulator proteins in real-time, in an in vivo environment.

Compared with SARS-CoV2 wild type's spike protein, the SARS-CoV2 omicron's receptor binding motif has adopted a more SARS-CoV1 and/or bat/civet-like structure.

2021 ◽  
Author(s):  
Michael O. Glocker ◽  
Kwabena F. M. Opuni ◽  
Hans-Juergen Thiesen
Keyword(s):  
Free Energy ◽  
Receptor Binding ◽  
Free Energy Calculations ◽  
Viral Fitness ◽  
Spike Protein ◽  
Receptor Protein ◽  
Binding Motif ◽  
Energy Calculations ◽  
Selection Processes ◽  
Protein Receptor

Our study focuses on free energy calculations of SARS-Cov2 spike protein receptor binding motives (RBMs) from wild type and variants-of-concern with particular emphasis on currently emerging SARS- CoV2 omicron variants of concern (VOC). Our computational free energy analysis underlines the occurrence of positive selection processes that specify omicron host adaption and bring changes on the molecular level into context with clinically relevant observations. Our free energy calculations studies regarding the interaction of omicron's RBM with human ACE2 shows weaker binding to ACE2 than alpha's, delta's, or wild type's RBM. Thus, less virus is predicted to be generated in time per infected cell. Our mutant analyses predict with focus on omicron variants a reduced spike-protein binding to ACE2--receptor protein possibly enhancing viral fitness / transmissibility and resulting in a delayed induction of danger signals as trade-off. Finally, more virus is produced but less per cell accompanied with delayed Covid-19 immunogenicity and pathogenicity. Regarding the latter, more virus is assumed to be required to initiate inflammatory immune responses.

Structure, stability and folding of the α-helix

2001 ◽  
Vol 68 ◽  
pp. 95-110 ◽  
Author(s):  
Andrew J. Doig ◽  
Charles D. Andrew ◽  
Duncan A. E. Cochran ◽  
Eleri Hughes ◽  
Simon Penel ◽  
...  
Keyword(s):  
Hydrogen Bonding ◽  
Hydrophobic Interactions ◽  
Data Bank ◽  
Site Directed Mutagenesis ◽  
Model Systems ◽  
Side Chain ◽  
Structure Stability ◽  
Helical Peptides ◽  
Vast Number ◽  
Α Helix

Pauling first described the α-helix nearly 50 years ago, yet new features of its structure continue to be discovered, using peptide model systems, site-directed mutagenesis, advances in theory, the expansion of the Protein Data Bank and new experimental techniques. Helical peptides in solution form a vast number of structures, including fully helical, fully coiled and partly helical. To interpret peptide results quantitatively it is essential to use a helix/coil model that includes the stabilities of all these conformations. Our models now include terms for helix interiors, capping, side-chain interactions, N-termini and 310-helices. The first three amino acids in a helix (N1, N2 and N3) and the preceding N-cap are unique, as their amide NH groups do not participate in backbone hydrogen bonding. We surveyed their structures in proteins and measured their amino acid preferences. The results are predominantly rationalized by hydrogen bonding to the free NH groups. Stabilizing side-chain-side-chain energies, including hydrophobic interactions, hydrogen bonding and polar/non-polar interactions, were measured accurately in helical peptides. Helices in proteins show a preference for having approximately an integral number of turns so that their N- and C-caps lie on the same side. There are also strong periodic trends in the likelihood of terminating a helix with a Schellman or αL C-cap motif. The kinetics of α-helix folding have been studied with stopped-flow deep ultraviolet circular dichroism using synchrotron radiation as the light source; this gives a far superior signal-to-noise ratio than a conventional instrument. We find that poly(Glu), poly(Lys) and alanine-based peptides fold in milliseconds, with longer peptides showing a transient overshoot in helix content.

scholarly journals Optimal Anchoring of a Urea-based Foldamer Inhibitor of ASF1 Histone Chaperone Through Backbone Plasticity

2020 ◽  
Author(s):  
Johanne Mbianda ◽  
May Bakail ◽  
Christophe André ◽  
Gwenaëlle Moal ◽  
Marie E. Perrin ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Histone Chaperone ◽  
Protein Protein Interactions ◽  
Protein Surface ◽  
Chromatin Dynamics ◽  
Correct Orientation ◽  
Surface Recognition ◽  
Binding Interface ◽  
Helical Peptide ◽  
Α Helix

<p><b>Sequence-specific oligomers with predictable folding patterns, i.e. foldamers provide new opportunities to mimic α-helical peptides and design inhibitors of protein-protein interactions. One major hurdle of this strategy is to retain the correct orientation of key side chains involved in protein surface recognition. Here, we show that the structural plasticity of a foldamer backbone may significantly contribute to the required spatial adjustment for optimal interaction with the protein surface. By using oligoureas as α-helix mimics, we designed a foldamer/peptide hybrid inhibitor of histone chaperone ASF1, a key regulator of chromatin dynamics. The crystal structure of its complex with ASF1 reveals a striking plasticity of the urea backbone, which adapts to the ASF1 surface to maintain the same binding interface. One additional benefit of generating ASF1 ligands with non-peptide oligourea segments is the resistance to proteolysis in human plasma which was highly improved compared to the cognate α-helical peptide. </b></p>

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