scholarly journals Molecular dynamics reveals complex compensatory effects of ionic strength on the SARS-CoV-2 Spike/hACE-2 interaction

2020 ◽  
Author(s):  
Anacleto Silva de Souza ◽  
Jose D. Rivera ◽  
Vitor Medeiros ◽  
Pingju Ge ◽  
Robson Francisco de Souza ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Ionic Strength ◽  
Protein Conformation ◽  
Hydrophobic Interactions ◽  
Virus Entry ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Computational Simulations ◽  
Wide Range ◽  
Host Cell Surface

The SARS-CoV-2 pandemic has already killed more than 800,000 people worldwide. To gain entry, the virus uses its spike protein to bind to host hACE-2 receptors on the host cell surface and mediate fusion between viral and cell membranes. As initial steps leading to virus entry involves significant changes in protein conformation as well as in the electrostatic environment in the vicinity of the spike-hACE-2 complex, we explored the sensitivity of the interaction to changes in ionic strength through computational simulations and surface plasmon resonance. We identified two regions in the receptor-binding domain (RBD), E1 and E2, which interact differently with hACE-2. At high salt concentration, E2-mediated interactions are weakened but are compensated by strengthening E1-mediated hydrophobic interactions. These results provide a detailed molecular understanding of spike RBD/hACE-2 complex formation and stability under a wide range of ionic strengths.

ReaxFF-based molecular dynamics simulation of the interaction between plasma ROS and the receptor-binding domain of the spike protein in the capsid protein of SARS-CoV-2

2021 ◽  
Author(s):  
Huichao Wang ◽  
Tong Zhao ◽  
Shuhui Yang ◽  
Liang Zou ◽  
Xiaolong Wang ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Amino Acid ◽  
Capsid Protein ◽  
Receptor Binding ◽  
Hydrogen Abstraction ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Amino Acid Residues ◽  
Global Epidemic

Abstract Under the severe situation of the current global epidemic, researchers have been working hard to find a reliable way to suppress the infection of the virus and prevent the spread of the epidemic. Studies have shown that the recognition and binding of human angiotensin-converting enzyme 2 (ACE2) by the receptor-binding domain (BRD) of spike protein on the surface of SARS-CoV-2 is a crucial step for SARS-CoV-2 to invade human receptor cells, and blocking this process can inhibit the virus from invading human normal cells. Plasma treatment can disrupt the structure of the RBD and effectively block the binding process. However, the mechanism by which plasma blocks the recognition and binding between the two is not clear. In this study, reaction process between reactive oxygen species (ROS) in plasma and the molecular model of RBD was simulated using a reactive molecular dynamics method. The results showed that the destruction of RBD molecule by ROS was triggered by hydrogen abstraction reactions. O and OH abstracted H atoms from RBD, while the H atoms of H2O2 and HO2 were abstracted by RBD. The hydrogen abstraction resulted in the breakage of C-H, N-H, O-H and C=O bonds and the formation of C=C, C=N bonds. The addition reaction of OH increased the number of O-H bonds and caused the formation of C-O, N-O and O-H bonds. The dissociation of N-H bonds led to the destruction of the original structure of peptide bonds and amino acid residues, change the type of amino acid residues, and caused the conversion of N-C and N=C, C=O and C-O. The simulation partially elucidated the microscopic mechanism of the interaction between ROS in plasma and the capsid protein of SARS-CoV-2, providing theoretical support for the control of SARS-CoV-2 infection by plasma, a contribution to overcoming the global epidemic problem.

scholarly journals Convergent Antibody Responses to SARS-CoV-2 Infection in Convalescent Individuals

2020 ◽  
Author(s):  
Davide F. Robbiani ◽  
Christian Gaebler ◽  
Frauke Muecksch ◽  
Julio C. C. Lorenzi ◽  
Zijun Wang ◽  
...  
Keyword(s):  
Virus Entry ◽  
Protein S ◽  
Memory B Cells ◽  
Antibody Responses ◽  
Spike Protein ◽  
Human Antibody ◽  
Receptor Binding Domain ◽  
Single Digit ◽  
Specific Antibodies ◽  
Specific Memory

AbstractDuring the COVID-19 pandemic, SARS-CoV-2 infected millions of people and claimed hundreds of thousands of lives. Virus entry into cells depends on the receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S). Although there is no vaccine, it is likely that antibodies will be essential for protection. However, little is known about the human antibody response to SARS-CoV-21–5. Here we report on 149 COVID-19 convalescent individuals. Plasmas collected an average of 39 days after the onset of symptoms had variable half-maximal neutralizing titers ranging from undetectable in 33% to below 1:1000 in 79%, while only 1% showed titers >1:5000. Antibody cloning revealed expanded clones of RBD-specific memory B cells expressing closely related antibodies in different individuals. Despite low plasma titers, antibodies to three distinct epitopes on RBD neutralized at half-maximal inhibitory concentrations (IC50s) as low as single digit ng/mL. Thus, most convalescent plasmas obtained from individuals who recover from COVID-19 do not contain high levels of neutralizing activity. Nevertheless, rare but recurring RBD-specific antibodies with potent antiviral activity were found in all individuals tested, suggesting that a vaccine designed to elicit such antibodies could be broadly effective.

scholarly journals Diversity of Coronavirus Receptors

2021 ◽  
Author(s):  
Pritha Ghosh ◽  
Savita Jayaram ◽  
Dhruti Patwardhan ◽  
Saranya Marimuthu ◽  
Patrick Lenehan ◽  
...  
Keyword(s):  
Animal Species ◽  
Protein S ◽  
Human Infection ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Infection Cycle ◽  
Wide Range ◽  
Underlying Mechanisms ◽  
Phylogenetic Lineages ◽  
Host Cell Membranes

Several recent surges in COVID-19 cases due to newly emerging variant strains of SARS-CoV-2 with greater transmissibility have highlighted the virus’s capability to directly modulate spike-ACE2 interactions and promote immune evasion by sterically masking the immunogenic epitopes. Recently, there have also been reports of the bidirectional transfer of coronavirus between different animal species and humans. The ability of coronavirus to infect and adapt to a wide range of hosts can be attributed to new variants that modify the molecular recognition profile of the spike protein (S protein). The receptor-binding domain of the spike protein specifically interacts with key host receptor molecules present on the host cell membranes to gain entry into the host and begin the infection cycle. In this review, we discuss the molecular, structural, and functional diversity associated with the coronavirus receptors across their different phylogenetic lineages and its relevance to various symptomatology in the rapid human-to-human infection in COVID-19 patients, tropism, and zoonosis. Despite this seeming diversity of host receptors, there may be some common underlying mechanisms that influence the host range, virus transmissibility, and pathogenicity. Understanding these mechanisms may be crucial in not only controlling the ongoing pandemic but also help in stopping the resurgence of such virus threats in the future.

scholarly journals Human Coronavirus 229E: Receptor Binding Domain and Neutralization by Soluble Receptor at 37°C

2003 ◽  
Vol 77 (7) ◽  
pp. 4435-4438 ◽  
Author(s):  
Jamie J. Breslin ◽  
Irene Mørk ◽  
M. K. Smith ◽  
Lotte K. Vogel ◽  
Erin M. Hemmila ◽  
...  
Keyword(s):  
Amino Acids ◽  
Receptor Binding ◽  
Conformational Changes ◽  
Virus Entry ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Soluble Receptor ◽  
Human Coronavirus ◽  
Virus Receptor ◽  
Human Coronavirus 229E

ABSTRACT Truncated human coronavirus HCoV-229E spike glycoproteins containing amino acids 407 to 547 bound to purified, soluble virus receptor, human aminopeptidase N (hAPN). Soluble hAPN neutralized the infectivity of HCoV-229E virions at 37°C, but not 4°C. Binding of hAPN may therefore trigger conformational changes in the viral spike protein at 37°C that facilitate virus entry.

scholarly journals Molecular Dynamics Analysis of a Flexible Loop at the Binding Interface of the SARS-CoV-2 Spike Protein Receptor-Binding Domain

2021 ◽  
Author(s):  
Jonathan K. Williams ◽  
Baifan Wang ◽  
Andrew Sam ◽  
Cody L. Hoop ◽  
David A. Case ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Receptor Binding ◽  
Binding Domain ◽  
Conformational Space ◽  
Spike Protein ◽  
Conformational Ensemble ◽  
Receptor Binding Domain ◽  
Loop Modeling ◽  
Binding Interface ◽  
Protein Receptor

AbstractSince the identification of the SARS-CoV-2 virus as the causative agent of the current COVID-19 pandemic, considerable effort has been spent characterizing the interaction between the Spike protein receptor-binding domain (RBD) and the human angiotensin converting enzyme 2 (ACE2) receptor. This has provided a detailed picture of the end point structure of the RBD-ACE2 binding event, but what remains to be elucidated is the conformation and dynamics of the RBD prior to its interaction with ACE2. In this work we utilize molecular dynamics simulations to probe the flexibility and conformational ensemble of the unbound state of the receptor-binding domain from SARS-CoV-2 and SARS-CoV. We have found that the unbound RBD has a localized region of dynamic flexibility in Loop 3 and that mutations identified during the COVID-19 pandemic in Loop 3 do not affect this flexibility. We use a loop-modeling protocol to generate and simulate novel conformations of the CoV2-RBD Loop 3 region that sample conformational space beyond the ACE2 bound crystal structure. This has allowed for the identification of interesting substates of the unbound RBD that are lower energy than the ACE2-bound conformation, and that block key residues along the ACE2 binding interface. These novel unbound substates may represent new targets for therapeutic design.

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 Discovery and in-vitro evaluation of potent SARS-CoV-2 entry inhibitors

2021 ◽  
Author(s):  
Arpan Acharya ◽  
Kabita Pandey ◽  
Michellie Thurman ◽  
Elizabeth Klug ◽  
Jay Trivedi ◽  
...  
Keyword(s):  
Virus Entry ◽  
Vero Cells ◽  
Spike Protein ◽  
Entry Inhibitor ◽  
Receptor Binding Domain ◽  
Human Bronchial Epithelial Cells ◽  
Computer Aided Drug Design ◽  
Bronchial Epithelial ◽  
Entry Inhibitors

SARS-CoV-2 infection initiates with the attachment of spike protein to the ACE2 receptor. While vaccines have been developed, no SARS-CoV-2 specific small molecule inhibitors have been approved. Herein, utilizing the crystal structure of the ACE2/Spike receptor binding domain (S-RBD) complex in computer-aided drug design (CADD) approach, we docked ~8 million compounds within the pockets residing at S-RBD/ACE2 interface. Five best hits depending on the docking score, were selected and tested for their in vitro efficacy to block SARS-CoV-2 replication. Of these, two compounds (MU-UNMC-1 and MU-UNMC-2) blocked SARS-CoV-2 replication at sub-micromolar IC50 in human bronchial epithelial cells (UNCN1T) and Vero cells. Furthermore, MU-UNMC-2 was highly potent in blocking the virus entry by using pseudoviral particles expressing SARS-CoV-2 spike. Finally, we found that MU-UNMC-2 is highly synergistic with remdesivir (RDV), suggesting that minimal amounts are needed when used in combination with RDV, and has the potential to develop as a potential entry inhibitor for COVID-19.

scholarly journals Key Residues of the Receptor Binding Domain in the Spike Protein of SARS-CoV-2 Mediating the Interactions with ACE2: A Molecular Dynamics Study

Nanoscale ◽  
2021 ◽  
Author(s):  
Yanmei Yang ◽  
Yunju Zhang ◽  
Yuanyuan Qu ◽  
Chao Zhang ◽  
Xuewei Liu ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Global Health ◽  
Receptor Binding ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Wide Spread ◽  
Key Residues

The wide spread of coronavirus disease 2019 (COVID-19) has declared a global health emergency. As one of the most important targets for antibody and drug developments, Spike RBD-ACE2 interface has...

Sign in / Sign up

Export Citation Format

Share Document