Differential Dynamic Behavior of Prefusion Spike Proteins of SARS Coronaviruses 1 and 2

Within the last two decades, severe acute respiratory syndrome (SARS) coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2) have caused two major outbreaks. For reasons yet to be fully understood the COVID-19 outbreak caused by SARS-CoV-2 has been significantly more widespread than the 2003 SARS epidemic caused by SARS-CoV-1, despite striking similarities between the two viruses. One of the most variable genes differentiating SARS-CoV-1 and SARS-CoV-2 is the S gene that encodes the spike glycoprotein. This protein mediates a crucial step in the infection, i.e., host cell recognition and viral entry, which starts with binding to the host cell angiotensin converting enzyme 2 (ACE2) protein for both viruses. Recent structural and functional studies have shed light on the differential binding behavior of the SARS-CoV-1 and SARS-CoV-2 spike proteins. In particular, cryogenic electron microscopy (cryo-EM) studies show that ACE2 binding is preceded by a large-scale conformational change in the spike protein to expose the receptor binding domain (RBD) to its binding partner. Unfortunately, these studies do not provide detailed information on the dynamics of this activation process. Here, we have used an extensive set of unbiased and biased microsecond-timescale all-atom molecular dynamics (MD) simulations of SARS-CoV-1 and SARS-CoV-2 spike protein ectodomains in explicit solvent to determine the differential behavior of spike protein activation in the two viruses. Our results based on nearly 50 microseconds of equilibrium and nonequilibrium MD simulations indicate that the active form of the SARS-CoV-2 spike protein is considerably more stable than the active SARS-CoV-1 spike protein. Unlike the active SARS-CoV-2 spike, the active SARS-CoV-1 spike spontaneously undergoes a large-scale conformational transition to a pseudo-inactive state, which occurs in part due to interactions between the N-terminal domain (NTD) and RBD that are absent in the SARS-CoV-2 spike protein. Steered MD (SMD) simulations indicate that the energy barriers between active and inactive states are comparatively lower for the SARS-CoV-1 spike protein. Based on these results, we hypothesize that the greater propensity of the SARS-CoV-2 spike protein to remain in the active conformation contributes to the higher transmissibility of SARS-CoV-2 in comparison to SARS-CoV-1. These results strongly suggest that the differential binding behavior of the active SARS-CoV-1 and 2 spike proteins is not merely due to differences in their RBDs as other domains of the spike protein such as the NTD could play a crucial role in the effective binding process, which involves the prebinding activation. Therefore, our hypothesis predicts that mutations in regions such as the NTD, which is not directly involved in binding, may lead to a change in the effective binding behavior of the coronavirus.

Download Full-text

Molecular Interactions of Fullerene-Based Derivatives and SARS-CoV-2

10.21203/rs.3.rs-40770/v1 ◽

2020 ◽

Author(s):

Alaa El-DinA. Gawad ◽

Ahmed M. Bayoumy ◽

Medhat A. Ibrahim

Keyword(s):

Molecular Docking ◽

Hydrogen Bonds ◽

Binding Sites ◽

Electrostatic Interactions ◽

Binding Mode ◽

Spike Protein ◽

Promising Candidate ◽

Binding Behavior ◽

Computer Aided ◽

Differential Binding

Abstract There are no expedient proven to stop the outbreak of SARS-CoV-2 at this phase. This leads to diversity of endeavors to find out the effective drug or vaccine. One of these possibilities is to exploit the unique characteristics of fullerene-based derivatives. A computer-aided method (molecular docking) was applied to assess the differential binding behavior of these compounds and determining hydrophobic forces, electrostatic interactions, and hydrogen bonds played vital roles in the interactions with SARS-CoV-2 spike protein. The molecular docking calculation clarifies the binding mode and the binding sites may facilitate the development of new or improved therapeutic regimes effective against COVID-19. Fulleropyrrolidine-NH2 seems to be promising candidate for interacting with SARS-CoV-2 binding site.

Download Full-text

Deciphering collaborative sidechain motions in proteins during molecular dynamics simulations

Scientific Reports ◽

10.1038/s41598-020-72766-1 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Bruck Taddese ◽

Antoine Garnier ◽

Hervé Abdi ◽

Daniel Henrion ◽

Marie Chabbert

Keyword(s):

Molecular Dynamics ◽

Large Scale ◽

Conformational Transition ◽

Transmembrane Helix ◽

Principal Component ◽

Dynamic Structure ◽

Md Simulations ◽

Outward Motion ◽

Dynamics Simulations

Abstract The dynamic structure of proteins is essential for their functions and may include large conformational transitions which can be studied by molecular dynamics (MD) simulations. However, details of these transitions are difficult to automatically track. To facilitate their analysis, we developed two scores of correlation between sidechain dihedral angles. The CIRCULAR and OMES scores are computed from, respectively, dihedral angle values and rotamer distributions. As a case study, we applied our methods to an activation-like transition of the chemokine receptor CXCR4, observed during accelerated MD simulations. The principal component analysis of the correlation matrices was consistent with the networking structure of the top ranking pairs. Both scores identify a set of residues whose “collaborative” sidechain rotamerization immediately preceded or accompanied the conformational transition of CXCR4. Detailed analysis of the sequential order of these rotamerizations suggests that an allosteric mechanism, involving the outward motion of an asparagine residue in transmembrane helix 3, might be a prerequisite to the large scale conformational transition of CXCR4. This case study provides the proof-of-concept that the correlation methods developed here are valuable exploratory techniques to help decipher complex reactional pathways.

Download Full-text

Sterically confined rearrangements of SARS-CoV-2 Spike protein control cell invasion

eLife ◽

10.7554/elife.70362 ◽

2021 ◽

Vol 10 ◽

Author(s):

Esteban Dodero-Rojas ◽

Jose N Onuchic ◽

Paul Charles Whitford

Keyword(s):

Host Cell ◽

Conformational Change ◽

Cell Invasion ◽

Large Scale ◽

Control Cell ◽

Spike Protein ◽

Fusion Peptides ◽

Structural Framework ◽

Host Membrane ◽

Transmembrane Pores

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly contagious, and transmission involves a series of processes that may be targeted by vaccines and therapeutics. During transmission, host cell invasion is controlled by a large-scale (200–300 Å) conformational change of the Spike protein. This conformational rearrangement leads to membrane fusion, which creates transmembrane pores through which the viral genome is passed to the host. During Spike-protein-mediated fusion, the fusion peptides must be released from the core of the protein and associate with the host membrane. While infection relies on this transition between the prefusion and postfusion conformations, there has yet to be a biophysical characterization reported for this rearrangement. That is, structures are available for the endpoints, though the intermediate conformational processes have not been described. Interestingly, the Spike protein possesses many post-translational modifications, in the form of branched glycans that flank the surface of the assembly. With the current lack of data on the pre-to-post transition, the precise role of glycans during cell invasion has also remained unclear. To provide an initial mechanistic description of the pre-to-post rearrangement, an all-atom model with simplified energetics was used to perform thousands of simulations in which the protein transitions between the prefusion and postfusion conformations. These simulations indicate that the steric composition of the glycans can induce a pause during the Spike protein conformational change. We additionally show that this glycan-induced delay provides a critical opportunity for the fusion peptides to capture the host cell. In contrast, in the absence of glycans, the viral particle would likely fail to enter the host. This analysis reveals how the glycosylation state can regulate infectivity, while providing a much-needed structural framework for studying the dynamics of this pervasive pathogen.

Download Full-text

Sterically-Confined Rearrangements of SARS-CoV-2 Spike Protein Control Cell Invasion

10.1101/2021.01.18.427189 ◽

2021 ◽

Author(s):

Esteban Dodero-Rojas ◽

José N. Onuchic ◽

Paul C. Whitford

Keyword(s):

Host Cell ◽

Conformational Change ◽

Cell Invasion ◽

Large Scale ◽

Control Cell ◽

Spike Protein ◽

Fusion Peptides ◽

Host Membrane ◽

Transmembrane Pores

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly contagious, and transmission involves a series of processes that may be targeted by vaccines and therapeutics. During transmission, host cell invasion is controlled by a large-scale conformational change of the Spike protein. This conformational rearrangement leads to membrane fusion, which creates transmembrane pores through which the viral genome is passed to the host. During Spike-protein-mediated fusion, the fusion peptides must be released from the core of the protein and associate with the host membrane. Interestingly, the Spike protein possesses many post-translational modifications, in the form of branched glycans that flank the surface of the assembly. Despite the large number of glycosylation sites, until now, the specific role of glycans during cell invasion has been unclear. Here, we propose that glycosylation is needed to provide sufficient time for the fusion peptides to reach the host membrane, otherwise the viral particle would fail to enter the host. To understand this process, an all-atom model with simplified energetics was used to perform thousands of simulations in which the protein transitions between the prefusion and postfusion conformations. These simulations indicate that the steric composition of the glycans induces a pause during the Spike protein conformational change. We additionally show that this glycan-induced delay provides a critical opportunity for the fusion peptides to capture the host cell. This previously-unrecognized role of glycans reveals how the glycosylation state can regulate infectivity of this pervasive pathogen.

Download Full-text

Exploring Conformational Transition of 2019 Novel Coronavirus Spike Glycoprotein Between Its Closed and Open States Using Molecular Dynamics Simulations

10.1101/2020.04.17.047324 ◽

2020 ◽

Author(s):

Mert Gur ◽

Elhan Taka ◽

Sema Zeynep Yilmaz ◽

Ceren Kilinc ◽

Umut Aktas ◽

...

Keyword(s):

Molecular Dynamics ◽

Host Cell ◽

Crystal Structures ◽

Critical Role ◽

Minimum Energy ◽

Md Simulations ◽

Host Cells ◽

Spike Protein ◽

Novel Coronavirus ◽

Open States

ABSTRACTSince its first recorded appearance in December 2019, a novel coronavirus (SARS-CoV-2) causing the disease COVID-19 has resulted in more than 2,000,000 infections and 128,000 deaths. Currently there is no proven treatment for COVID-19 and there is an urgent need for the development of vaccines and therapeutics. Coronavirus spike glycoproteins play a critical role in coronavirus entry into the host cells, as they provide host cell recognition and membrane fusion between virus and host cell. Thus, they emerged as popular and promising drug targets. Crystal structures of spike protein in its closed and open states were resolved very recently in March 2020. These structures comprise 77% of the sequence and provide almost the complete protein structure. Based on down and up positions of receptor binding domain (RBD), spike protein can be in a receptor inaccessible closed or receptor accessible open state, respectively. Starting from closed and open state crystal structures, and also 16 intermediate conformations, an extensive set of all-atom molecular dynamics (MD) simulations in the presence of explicit water and ions were performed. Simulations show that in its down position, RBD has significantly lower mobility compared to its up position; probably caused by the 6 interdomain salt bridges of RBD in down position compared to 3 in up position. Free energy landscapes based on MD simulations revealed a semi-open state located between closed and open states. Minimum energy pathway between down and up positions comprised a gradual salt bridge switching mechanism. Furthermore, although significantly lower than open state, ACE2 binding surface of RBD contained a partial solvent accessibility in its closed state.

Download Full-text

The Extended Intermediate of the SARS-CoV-2 Spike Protein uses Extreme Reach and Flexibility to Capture Host Cell Membranes

Biophysical Journal ◽

10.1016/j.bpj.2020.11.2027 ◽

2021 ◽

Vol 120 (3) ◽

pp. 321a

Author(s):

Rui Su ◽

Jin Zeng ◽

Sathish Thiyagarajan ◽

Ben O'Shaughnessy

Keyword(s):

Host Cell ◽

Cell Membranes ◽

Spike Protein ◽

Host Cell Membranes

Download Full-text

Exaptation of Retroviral Syncytin for Development of Syncytialized Placenta, Its Limited Homology to the SARS-CoV-2 Spike Protein and Arguments against Disturbing Narrative in the Context of COVID-19 Vaccination

Biology ◽

10.3390/biology10030238 ◽

2021 ◽

Vol 10 (3) ◽

pp. 238

Author(s):

Malgorzata Kloc ◽

Ahmed Uosef ◽

Jacek Z. Kubiak ◽

Rafik M. Ghobrial

Keyword(s):

Cell Membrane ◽

Host Cell ◽

Envelope Glycoprotein ◽

Mammalian Species ◽

Viral Envelope ◽

Spike Protein ◽

Mammalian Evolution ◽

Trophoblast Cells ◽

Host Cell Membrane ◽

Uterine Endometrium

Human placenta formation relies on the interaction between fused trophoblast cells of the embryo with uterine endometrium. The fusion between trophoblast cells, first into cytotrophoblast and then into syncytiotrophoblast, is facilitated by the fusogenic protein syncytin. Syncytin derives from an envelope glycoprotein (ENV) of retroviral origin. In exogenous retroviruses, the envelope glycoproteins coded by env genes allow fusion of the viral envelope with the host cell membrane and entry of the virus into a host cell. During mammalian evolution, the env genes have been repeatedly, and independently, captured by various mammalian species to facilitate the formation of the placenta. Such a shift in the function of a gene, or a trait, for a different purpose during evolution is called an exaptation (co-option). We discuss the structure and origin of the placenta, the fusogenic and non-fusogenic functions of syncytin, and the mechanism of cell fusion. We also comment on an alleged danger of the COVID-19 vaccine based on the presupposed similarity between syncytin and the SARS-CoV-2 spike protein.

Download Full-text

Role of Structural and Non-Structural Proteins and Therapeutic Targets of SARS-CoV-2 for COVID-19

Cells ◽

10.3390/cells10040821 ◽

2021 ◽

Vol 10 (4) ◽

pp. 821

Author(s):

Rohitash Yadav ◽

Jitendra Kumar Chaudhary ◽

Neeraj Jain ◽

Pankaj Kumar Chaudhary ◽

Supriya Khanra ◽

...

Keyword(s):

Host Cell ◽

Protein S ◽

Structural Similarity ◽

Cell Receptor ◽

Molecular Assembly ◽

The Body ◽

Spike Protein ◽

Structural Proteins ◽

Structural Protein ◽

Novel Coronavirus

Coronavirus belongs to the family of Coronaviridae, comprising single-stranded, positive-sense RNA genome (+ ssRNA) of around 26 to 32 kilobases, and has been known to cause infection to a myriad of mammalian hosts, such as humans, cats, bats, civets, dogs, and camels with varied consequences in terms of death and debilitation. Strikingly, novel coronavirus (2019-nCoV), later renamed as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and found to be the causative agent of coronavirus disease-19 (COVID-19), shows 88% of sequence identity with bat-SL-CoVZC45 and bat-SL-CoVZXC21, 79% with SARS-CoV and 50% with MERS-CoV, respectively. Despite key amino acid residual variability, there is an incredible structural similarity between the receptor binding domain (RBD) of spike protein (S) of SARS-CoV-2 and SARS-CoV. During infection, spike protein of SARS-CoV-2 compared to SARS-CoV displays 10–20 times greater affinity for its cognate host cell receptor, angiotensin-converting enzyme 2 (ACE2), leading proteolytic cleavage of S protein by transmembrane protease serine 2 (TMPRSS2). Following cellular entry, the ORF-1a and ORF-1ab, located downstream to 5′ end of + ssRNA genome, undergo translation, thereby forming two large polyproteins, pp1a and pp1ab. These polyproteins, following protease-induced cleavage and molecular assembly, form functional viral RNA polymerase, also referred to as replicase. Thereafter, uninterrupted orchestrated replication-transcription molecular events lead to the synthesis of multiple nested sets of subgenomic mRNAs (sgRNAs), which are finally translated to several structural and accessory proteins participating in structure formation and various molecular functions of virus, respectively. These multiple structural proteins assemble and encapsulate genomic RNA (gRNA), resulting in numerous viral progenies, which eventually exit the host cell, and spread infection to rest of the body. In this review, we primarily focus on genomic organization, structural and non-structural protein components, and potential prospective molecular targets for development of therapeutic drugs, convalescent plasm therapy, and a myriad of potential vaccines to tackle SARS-CoV-2 infection.

Download Full-text

Dynamics of Large-Scale Protein Conformational Transition and Docking Events using a Hybrid All-Atom Structure Based Model

Biophysical Journal ◽

10.1016/j.bpj.2011.11.1435 ◽

2012 ◽

Vol 102 (3) ◽

pp. 260a-261a

Author(s):

Ilaria Mereu ◽

Ludovico Sutto ◽

Francesco L. Gervasio

Keyword(s):

Large Scale ◽

Conformational Transition

Download Full-text

Molecular Dynamics Simulation of a Pullout Test on a Carbon Nanotube in a Polymer Matrix

MRS Proceedings ◽

10.1557/opl.2014.715 ◽

2014 ◽

Vol 1700 ◽

pp. 61-66

Author(s):

Guttormur Arnar Ingvason ◽

Virginie Rollin

Keyword(s):

Molecular Dynamics ◽

Polymer Matrix ◽

Large Scale ◽

Md Simulations ◽

Dynamics Simulation ◽

Atomistic Simulations ◽

Polymer Molecules ◽

Molecular Potential ◽

Pull Out ◽

Walled Carbon Nanotubes

ABSTRACTAdding single walled carbon nanotubes (SWCNT) to a polymer matrix can improve the delamination properties of the composite. Due to the complexity of polymer molecules and the curing process, few 3-D Molecular Dynamics (MD) simulations of a polymer-SWCNT composite have been run. Our model runs on the Large-scale Atomic/Molecular Massively Parallel Simulator (LAMMPS), with a COMPASS (Condensed phase Optimized Molecular Potential for Atomistic Simulations Studies) potential. This potential includes non-bonded interactions, as well as bonds, angles and dihedrals to create a MD model for a SWCNT and EPON 862/DETDA (Diethyltoluenediamine) polymer matrix. Two simulations were performed in order to test the implementation of the COMPASS parameters. The first one was a tensile test on a SWCNT, leading to a Young’s modulus of 1.4 TPa at 300K. The second one was a pull-out test of a SWCNT from an originally uncured EPON 862/DETDA matrix.

Download Full-text