scholarly journals Relationship between monomer packing and receptor binding domain pocket status in the spike trimer of SARS-CoV-2 variants

2021 ◽  
Author(s):  
Jim Warwicker
Keyword(s):  
Receptor Binding ◽  
Ph Dependence ◽  
Protein Structures ◽  
Binding Pocket ◽  
Spike Protein ◽  
Protein Charge ◽  
Neutral Ph ◽  
Binding Domains ◽  
Up States ◽  
The Relationship

Existence of a SARS-CoV-2 spike protein trimer form with closer packing between monomers when receptor binding domains (RBDs) are all down, locked as opposed to closed, has been associated with linoleic acid (LA) binding at neutral pH, or can occur at acidic pH in the absence of LA binding. The relationship between degree of closure of the LA binding pocket of the RBD, and monomer burial in the trimer, is examined for a range of spike protein structures, including those with D614G mutation, and that of the Delta variant (which also carries D614G). Some spike protein structures with this aspartic acid mutation show monomer packing approaching that of the locked form (at neutral pH, without LA binding) for two segments, a third (around the RBD) remains less closely packed. Analysis of other coronavirus RBD structures suggests that mutation of the RBD in spike protein of the Omicron variant could lead to LA binding pocket changes. It is proposed that these changes could lead to one of two consequences for the Omicron variant spike protein (which also has the D614G mutation), at neutral pH and without LA binding, either easier access to a locked form throughout that leads to cooperative transitions between all RBD down and all RBD up, or maintenance of a spike trimer with locked characteristics C-terminal to the RBD at the same time as the RBD is free to transit between down and up states. The situation may also be impacted by spike protein charge mutations in the Omicron lineage that alter pH-dependence around the RBD, in a similar way to the changes induced elsewhere by D614G.

scholarly journals Unraveling the stability landscape of mutations in the SARS-CoV-2 receptor-binding domain

2020 ◽  
Author(s):  
Mohamed Raef Smaoui ◽  
Hamdi Yahyaoui
Keyword(s):  
Receptor Binding ◽  
Single Point ◽  
Protein Structures ◽  
Point Mutations ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Point Mutant ◽  
The Stability ◽  
Spike Proteins

Abstract The interaction between the receptor-binding domain of the SARS-CoV-2 spike glycoprotein and the ACE2 enzyme is believed to be the entry point of the virus into various cells in the body, including the lungs, heart, liver, and kidneys. The current focus of several therapeutic design efforts explore attempts at affecting the binding interaction between the two proteins to limit the activity of the virus and disease progression. In this work, we analyze the stability of the spike protein under all possible single-point mutations in the receptor-binding domain and computationally explore mutations that can affect the binding with the ACE2 enzyme. We unravel the mutation landscape of the receptor region and assess the toxicity potential of single and multi-point mutations, generating insights for future vaccine efforts on potential mutations that might further stabilize the spike protein and increase its infectivity. We developed a tool, called SpikeMutator, to construct full atomic protein structures of the mutant spike proteins and shared a database of 3,800 single-point mutant structures. We analyzed the recent 65,000 reported spike sequences across the globe and observed the emergence of stable multi-point mutant structures. Using the landscape, we searched through 7.5 million possible 2-point mutation combinations and report that the (R355D K424E) mutation produces one of the strongest spike proteins that therapeutic efforts should investigate for the sake of developing an effective vaccine.

scholarly journals SARS-CoV-2 Prion-Like Domains in Spike Proteins Enables Higher Affinity to ACE2

2020 ◽  
Author(s):  
George Tetz ◽  
Victor Tetz
Keyword(s):  
Receptor Binding ◽  
Cell Receptor ◽  
Binding Domain ◽  
Spike Protein ◽  
Striking Difference ◽  
Receptor Binding Domain ◽  
Viral Receptor ◽  
Functional Roles ◽  
Binding Domains ◽  
Spike Proteins

Currently, the world is struggling with the coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Prion-like domains are critical for virulence and the development of therapeutic targets; however, the prion-like domains in the SARS-CoV-2 proteome have not been analyzed. In this in silico study, using the PLAAC algorithm, we identified the presence of prion-like domains in SARS-CoV-2 spike protein. Compared with other viruses, a striking difference was observed in the distribution of prion-like domains in the spike, since SARS-CoV-2 was the only coronavirus with a prion-like domain found in the receptor-binding domain of the S1 region of the spike protein. The presence and unique distribution of prion-like domains in the SARS-CoV-2 receptor-binding domains of spike proteins is particularly interesting, since although SARS-CoV-2 and SARS-CoV S share the same host cell receptor, angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 demonstrates a 10- to 20-fold higher affinity for ACE2. Finally, we identified prion-like domains in the α1 helix of the ACE2 receptor that interacts with the viral receptor-binding domain of SARS-CoV-2. Taken together, the present findings indicate that the identified PrDs in the SARS-CoV-2 receptor-binding domain (RBD) and ACE2 region that interacts with RBD have important functional roles in viral adhesion and entry.

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 Fusion Promotion by a Paramyxovirus Hemagglutinin-Neuraminidase Protein: pH Modulation of Receptor Avidity of Binding Sites I and II

2007 ◽  
Vol 81 (17) ◽  
pp. 9152-9161 ◽  
Author(s):  
Laura M. Palermo ◽  
Matteo Porotto ◽  
Olga Greengard ◽  
Anne Moscona
Keyword(s):  
Host Cell ◽  
Receptor Binding ◽  
Viral Entry ◽  
Ph Dependence ◽  
Initial Step ◽  
Viral Envelope ◽  
Respiratory Pathogen ◽  
Receptor Binding Site ◽  
Host Cell Membrane ◽  
Neutral Ph

ABSTRACT Paramyxoviruses, including the childhood respiratory pathogen human parainfluenza virus type 3 (HPIV3), possess an envelope protein hemagglutinin-neuraminidase (HN) that has receptor-cleaving (neuraminidase), as well as receptor-binding, activity. HN is a type II transmembrane glycoprotein, present on the surface of the virus as a tetramer composed of two dimers. HN is also essential for activating the fusion protein (F) to mediate merger of the viral envelope with the host cell membrane. This initial step of viral entry occurs at the host cell surface at neutral pH. The HN molecule carries out these three different critical activities at specific points in the process of viral entry, and understanding the regulation of these activities is key for the design of strategies that block infection. One bifunctional site (site I) on the HN of HPIV3 possesses both receptor binding and neuraminidase activities, and we recently obtained experimental evidence for a second receptor binding site (site II) on HPIV3 HN. Mutation of HN at specific residues at this site, which is next to the HN dimer interface, confers enhanced fusion properties, without affecting neuraminidase activity or receptor binding at neutral pH. We now demonstrate that mutations at this site II, as well as at site I, confer pH dependence on HN′s receptor avidity. These mutations permit pH to modulate the binding and fusion processes of the virus, potentially providing regulation at specific stages of the viral life cycle.

scholarly journals Predicted pH-dependent stability of SARS-CoV-2 spike protein trimer from interfacial acidic groups

2021 ◽  
Author(s):  
Vanessa R Lobo ◽  
Jim Warwicker
Keyword(s):  
Electron Microscopy ◽  
Receptor Binding ◽  
Ph Dependence ◽  
Spike Protein ◽  
Ph Effects ◽  
Large Set ◽  
Acidic Ph ◽  
Receptor Binding Domain ◽  
Cryo Electron Microscopy ◽  
Ph Dependent

Transition between receptor binding domain (RBD) up and down forms of the SARS-CoV-2 spike protein trimer is coupled to receptor binding and is one route by which variants can alter viral properties. It is becoming apparent that key roles in the transition are played by pH and a more compact closed form, termed locked. Calculations of pH-dependence are made for a large set of spike trimers, including locked form trimer structures that have recently become available. Several acidic sidechains become sufficiently buried in the locked form to give a predicted pH-dependence in the mild acidic range, with stabilisation of the locked form as pH reduces from 7.5 to 5, consistent with emerging characterisation by cryo-electron microscopy. The calculated pH effects in pre-fusion spike trimers are modulated mainly by aspartic acid residues, rather than the more familiar histidine role at mild acidic pH. These acidic sidechains are generally surface located and weakly interacting when not in a locked conformation. In this model, their replacement (perhaps with asparagine) would remove the pH-dependent destabilisation of locked spike trimer conformations, and increase their recovery at neutral pH. This would provide an alternative or supplement to the insertion of disulphide linkages for stabilising spike protein trimers, with potential relevance for vaccine design.

scholarly journals Phospholipids dock SARS-CoV-2 spike protein via hydrophobic interactions: a minimal in-silico study of lecithin nasal spray therapy

2021 ◽  
Author(s):  
Muhammad Nawaz Qaisrani ◽  
Jawad Ur Rehman ◽  
Roman Belousov ◽  
Elham Moharramzadeh Goliaei ◽  
Ivan Girotto ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Viral Infections ◽  
Hydrophobic Interactions ◽  
Chemical Properties ◽  
Binding Energies ◽  
Spike Protein ◽  
Binding Motif ◽  
Binding Domains ◽  
Preferential Binding ◽  
Dynamics Simulations

<div><div><div><p>Understanding the physical and chemical properties of viral infections at molecular scales is a major challenge for the scientific community more so with the outbreak of global pandemics. There is currently a lot of effort being placed in identifying molecules that could act as putative drugs or blockers of viral molecules. In this work, we computationally explore the importance in antiviral activity of a less studied class of molecules, namely surfactants. We employ all-atoms molecular dynamics simulations to study the interaction between the receptor-binding domain of the SARS-CoV-2 spike protein and the phospholipid lecithin (POPC), in water. Our microsecond simulations show a preferential binding of lecithin to the receptor-binding motif of SARS-CoV-2 with binding energies significantly larger than kBT. Furthermore, hydrophobic interactions in- volving lecithin non-polar tails dominate these binding events, which are also accompanied by dewetting of the receptor binding motif. Through an analysis of fluctuations in the radius of gyra- tion of the receptor-binding domains, its contact maps with lecithin molecules, and distributions of water molecules near the binding region, we elucidate molecular interactions that may play an important role in interactions involving surfactant-type molecules and viruses. We discuss our minimal computational model in the context of lecithin-based liposomal nasal sprays as putative mitigating therapies for COVID-19.</p></div></div></div>

scholarly journals Unraveling the stability landscape of mutations in the SARS-CoV-2 receptor-binding domain

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mohamed Raef Smaoui ◽  
Hamdi Yahyaoui
Keyword(s):  
Receptor Binding ◽  
Single Point ◽  
Protein Structures ◽  
Point Mutations ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Point Mutant ◽  
The Stability ◽  
Spike Proteins

AbstractThe interaction between the receptor-binding domain (RBD) of the SARS-CoV-2 spike glycoprotein and the ACE2 enzyme is believed to be the entry point of the virus into various cells in the body, including the lungs, heart, liver, and kidneys. The current focus of several therapeutic design efforts explores attempts at affecting the binding potential between the two proteins to limit the activity of the virus and disease progression. In this work, we analyze the stability of the spike protein under all possible single-point mutations in the RBD and computationally explore mutations that can affect the binding with the ACE2 enzyme. We unravel the mutation landscape of the receptor region and assess the toxicity potential of single and multi-point mutations, generating insights for future vaccine efforts on mutations that might further stabilize the spike protein and increase its infectivity. We developed a tool, called SpikeMutator, to construct full atomic protein structures of the mutant spike proteins and shared a database of 3800 single-point mutant structures. We analyzed the recent 65,000 reported spike sequences across the globe and observed the emergence of stable multi-point mutant structures. Using the landscape, we searched through 7.5 million possible 2-point mutation combinations and report that the (R355D K424E) mutation produces one of the strongest spike proteins that therapeutic efforts should investigate for the sake of developing effective vaccines.

Polyphenolic Natural Products Active In Silico against SARS-CoV-2 Spike Receptor Binding Domains and Non-Structural Proteins – A Review

2021 ◽  
Vol 25 ◽  
Author(s):  
Mark Tristan Quimque ◽  
Kin Israel Notarte ◽  
Xela Amor Adviento ◽  
Mikhail Harvey Cabunoc ◽  
Von Novi de Leon ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Viral Entry ◽  
Treatment Options ◽  
Polyphenolic Compounds ◽  
Spike Protein ◽  
Structural Proteins ◽  
Cell Recognition ◽  
Post Translational Modifications ◽  
Binding Domains ◽  
Host Cell Recognition

: The ongoing Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic has been proven to be more severe than the previous coronavirus outbreaks due to the virus’ high transmissibility. With the emergence of new variants, this global phenomenon took on a more dramatic turn with many countries recently experiencing higher surges of confirmed cases and deaths. On top of this, the inadequacy of effective treatment options for COVID-19 aggravated the problem. As a way to address the unavailability of target-specific viral therapeutics, computational strategies have been employed to hasten and systematize the search. The objective of this review is to provide initial data highlighting the utility of polyphenols as potential prophylaxis or treatment for COVID-19. In particular, presented here are virtually screened polyphenolic compounds which showed potential as either antagonists to viral entry and host cell recognition through binding with various receptor-binding regions of SARS-CoV-2 spike protein or as inhibitors of viral replication and post-translational modifications through binding with essential SARS-CoV-2 non-structural proteins.

scholarly journals Analysis of Fluctuation in the Heme-Binding Pocket and Heme Distortion in Hemoglobin and Myoglobin

2021 ◽  
Author(s):  
Hiroko X. Kondo ◽  
Yu Takano
Keyword(s):  
Physical Properties ◽  
Protein Structures ◽  
Oxygen Affinity ◽  
Md Simulations ◽  
Data Bank ◽  
Binding Pocket ◽  
Protein Functions ◽  
Heme Distortion ◽  
The Relationship ◽  
Protein Environment

Heme is located in the active site of proteins and has diverse and important biological functions, such as electron transfer and oxygen transport and/or storage. The distortion of heme porphyrin is considered an important factor for the diverse functions of heme because it correlates with the physical properties of heme, such as oxygen affinity and redox potential. Therefore, clarification of the relationship between heme distortion and the protein environment is crucial in protein science. Here, we analyzed the fluctuation in heme distortion in the protein environment for hemoglobin and myoglobin using molecular dynamics (MD) simulations and quantum mechanical (QM) calculations. We also investigated the protein structures of hemoglobin and myoglobin stored in Protein Data Bank and found that heme is distorted along the doming mode, which correlates with its oxygen affinity, more prominently in the protein environment than in the isolated state, and the magnitude of distortion is different between hemoglobin and myoglobin. This tendency was also observed in the results of MD simulations and QM calculations. These results suggest that heme distortion is affected by its protein environment and fluctuates around its fitted conformation, leading to physical properties that are appropriate for protein functions.

scholarly journals COVID-19 dominant D614G mutation in the SARS-CoV-2 spike protein desensitizes its temperature-dependent denaturation

2021 ◽  
Author(s):  
Tzu-Jing Yang ◽  
Pei-Yu Yu ◽  
Yuan-Chih Chang ◽  
Chu-Wei Kuo ◽  
Kay-Hooi Khoo ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Vaccine Development ◽  
Spike Protein ◽  
Temperature Dependent ◽  
Dominant Form ◽  
Binding Domains ◽  
Cryo Electron Microscopy ◽  
The Impact ◽  
Multiple Receptor ◽  
Shed Light

AbstractThe D614G mutation in the spike protein of SARS-CoV-2 alters the fitness of the virus, making it the dominant form in the COVID-19 pandemic. Here we demonstrated by cryo-electron microscopy that the D614G mutation does not significantly perturb the structure of the spike protein, but multiple receptor binding domains are in an upward conformation poised for host receptor binding. The impact of the mutation lies in its ability to eliminate the unusual cold-induced unfolding characteristics, and to significantly increase the thermal stability under physiological pH. Our findings shed light on how the D614G mutation enhances the infectivity of SARS-CoV-2 through a stabilizing mutation, and suggest an approach for better design of spike-protein based conjugates for vaccine development.

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