Allosteric Control of Structural Mimicry and Mutational Escape in the SARS-CoV-2 Spike Protein Complexes with the ACE2 Decoys and Miniprotein Inhibitors: A Network-Based Approach for Mutational Profiling of Binding and Signaling

2021 ◽  
Author(s):  
Gennady M. Verkhivker ◽  
Steve Agajanian ◽  
Deniz Yasar Oztas ◽  
Grace Gupta
Keyword(s):  
Protein Complexes ◽  
Spike Protein ◽  
Allosteric Control ◽  
Mutational Profiling

scholarly journals Dissecting Molecular Determinants of Mutational Escape Mechanisms in the SARS-CoV-2 Spike Protein Complexes with Nanobodies: Atomistic Simulations and Ensemble-Based Deep Mutational Scanning of Protein Stability and Binding Interactions

2021 ◽  
Author(s):  
Gennady Verkhivker ◽  
Steve Agajanian ◽  
Deniz Yasar Oztas ◽  
Grace Gupta
Keyword(s):  
Molecular Mechanisms ◽  
Protein Complexes ◽  
Conformational Dynamics ◽  
Spike Protein ◽  
Atomistic Simulations ◽  
Binding Interactions ◽  
Mutational Profiling ◽  
Neutralizing Capacity ◽  
The Stability ◽  
Protein Response

Structural and biochemical studies have recently revealed a range of rationally engineered nanobodies with efficient neutralizing capacity against SARS-CoV-2 virus and resilience against mutational escape. In this work, we combined atomistic simulations and conformational dynamics analysis with the ensemble-based mutational profiling of binding interactions for a diverse panel of SARS-CoV-2 spike complexes with nanobodies. Using this computational toolkit, we identified dynamic signatures and binding affinity fingerprints for the SARS-CoV-2 spike protein complexes with nanobodies Nb6 and Nb20, VHH E, a pair combination VHH E+U, a biparatopic nanobody VHH VE, and a combination of CC12.3 antibody and VHH V/W nanobodies. Through ensemble-based deep mutational profiling of stability and binding affinities, we identify critical hotspots and characterize molecular mechanisms of SARS-CoV-2 spike protein binding with single ultra-potent nanobodies, nanobody cocktails and biparatopic nanobodies. By quantifying dynamic and energetic determinants of the SARS-CoV-2 S binding with nanobodies, we also examine the effects of circulating variants and escaping mutations. We found that mutational escape mechanisms may be controlled through structurally and energetically adaptable binding hotspots located in the host receptor-accessible binding epitope that are dynamically coupled to the stability centers in the distant epitope targeted by VHH U/V/W nanobodies. The results of this study suggested a mechanism in which through cooperative dynamic changes, nanobody combinations and biparatopic nanobody can modulate the global protein response and induce the increased resilience to common escape mutants.

scholarly journals Atomistic Simulations and Deep Mutational Scanning of Protein Stability and Binding Interactions in the SARS-CoV-2 Spike Protein Complexes with Nanobodies: Molecular Determinants of Mutational Escape Mechanisms

2021 ◽  
Author(s):  
Gennady Verkhivker ◽  
Steve Agajanian ◽  
Deniz Yasar Oztas ◽  
Grace Gupta
Keyword(s):  
Molecular Mechanisms ◽  
Protein Complexes ◽  
Conformational Dynamics ◽  
Spike Protein ◽  
Atomistic Simulations ◽  
Binding Interactions ◽  
Mutational Profiling ◽  
Neutralizing Capacity ◽  
The Stability ◽  
Protein Response

Structural and biochemical studies have recently revealed a range of rationally engineered nanobodies with efficient neutralizing capacity against SARS-CoV-2 virus and resilience against mutational escape. In this work, we combined atomistic simulations and conformational dynamics analysis with the ensemble-based mutational profiling of binding interactions for a diverse panel of SARS-CoV-2 spike complexes with nanobodies. Using this computational toolkit we identified dynamic signatures and binding affinity fingerprints for the SARS-CoV-2 spike protein complexes with nanobodies Nb6 and Nb20, VHH E, a pair combination VHH E+U, a biparatopic nanobody VHH VE, and a combination of CC12.3 antibody and VHH V/W nanobodies. Through ensemble-based deep mutational profiling of stability and binding affinities, we identify critical hotspots and characterize molecular mechanisms of SARS-CoV-2 spike protein binding with single ultra-potent nanobodies, nanobody cocktails and biparatopic nanobodies. By quantifying dynamic and energetic determinants of the SARS-CoV-2 S binding with nanobodies, we also examine the effects of circulating variants and escaping mutations. We found that mutational escape mechanisms may be controlled through structurally and energetically adaptable binding hotspots located in the host receptor-accessible binding epitope that are dynamically coupled to the stability centers in the distant epitope targeted by VHH U/V/W nanobodies. The results of this study suggested a mechanism in which through cooperative dynamic changes, nanobody combinations and biparatopic nanobody can modulate the global protein response and induce the increased resilience to common escape mutants.

scholarly journals In-Silico evidence for two receptors based strategy of SARS-CoV-2

2020 ◽  
Author(s):  
Edoardo Milanetti ◽  
Mattia Miotto ◽  
Lorenzo Di Rienzo ◽  
Michele Monti ◽  
Giorgio Gosti ◽  
...  
Keyword(s):  
Protein Complexes ◽  
General Procedure ◽  
Spike Protein ◽  
Geometrical Shape ◽  
Upper Airways ◽  
Protein Surfaces ◽  
Angiotensin Converting Enzyme 2 ◽  
Shape Complementarity ◽  
Dual Strategy ◽  
Relationship Of

We propose a novel numerical method able to determine efficiently and effectively the relationship of complementarity between portions of protein surfaces. This innovative and general procedure, based on the representation of the molecular iso-electron density surface in terms of 2D Zernike polynomials, allows the rapid and quantitative assessment of the geometrical shape complementarity between interacting proteins, that was unfeasible with previous methods. We first tested the method with a large dataset of known protein complexes obtaining an overall area under the ROC curve of 0.76 in the blind recognition of binding sites and then applied it to investigate the features of the interaction between the Spike protein of SARS-CoV-2 and human cellular receptors. Our results indicate that SARS-CoV-2 uses a dual strategy: its spike protein could also interact with sialic acid receptors of the cells in the upper airways, in addition to the known interaction with Angiotensin-converting enzyme 2.

scholarly journals AI-based Spectroscopic Monitoring of Real-time Interactions between SARS-CoV-2 and Human ACE2

2020 ◽  
Author(s):  
Sheng Ye ◽  
Guozhen Zhang ◽  
Jun Jiang
Keyword(s):  
Machine Learning ◽  
Real Time ◽  
Protein Dynamics ◽  
Structural Information ◽  
Protein Complexes ◽  
Spike Protein ◽  
Proof Of Concept ◽  
Spectroscopy Study ◽  
Time Resolved ◽  
Spectroscopic Monitoring

<div> <p>Here we demonstrate by a proof-of-concept simulation of IR spectra of complex of spike protein of SARS-CoV-2 and human ACE2, that a time-resolved spectroscopy may monitor the real-time structural information of the protein-protein complexes of interest, with the help of a machine learning protocol. The significant speedup of our approach relative to conventional quantum chemistry approach suggests a promising way of accelerating the development of real-time spectroscopy study of protein dynamics.</p> </div>

scholarly journals AI-based Spectroscopic Monitoring of Real-time Interactions between SARS-CoV-2 and Human ACE2

2020 ◽  
Author(s):  
Sheng Ye ◽  
Guozhen Zhang ◽  
Jun Jiang
Keyword(s):  
Machine Learning ◽  
Real Time ◽  
Protein Dynamics ◽  
Structural Information ◽  
Protein Complexes ◽  
Spike Protein ◽  
Proof Of Concept ◽  
Spectroscopy Study ◽  
Time Resolved ◽  
Spectroscopic Monitoring

<div> <p>Here we demonstrate by a proof-of-concept simulation of IR spectra of complex of spike protein of SARS-CoV-2 and human ACE2, that a time-resolved spectroscopy may monitor the real-time structural information of the protein-protein complexes of interest, with the help of a machine learning protocol. The significant speedup of our approach relative to conventional quantum chemistry approach suggests a promising way of accelerating the development of real-time spectroscopy study of protein dynamics.</p> </div>

scholarly journals How Does the Novel Coronavirus Interact with the Human ACE2 Enzyme? A Thermodynamic Answer

2020 ◽  
Author(s):  
Jones de Andrade ◽  
Paulo Fernando Bruno Gonçalves ◽  
Paulo Augusto Netz
Keyword(s):  
Free Energy ◽  
Protein Complexes ◽  
Minimum Free Energy ◽  
New Drugs ◽  
Host Cells ◽  
Spike Protein ◽  
Health Concern ◽  
Novel Coronavirus ◽  
Dynamics Simulations ◽  
Free Energy Of Binding

<p>The SARS-CoV-2 coronavirus pandemic is certainly the most important public health concern today. Until now there are no vaccines or treatments available, despite intensive international efforts. One of the targets for new drugs is the Coronavirus Spike Protein, responsible for its binding and entry into the host cells. The Receptor Binding Domain (RBD) found at the Spike Protein recognizes the human angiotensin-converting enzyme 2 (hACE2). The present in silico study discuss structural and thermodynamic aspects of the protein complexes involving the RBD’s from the 2002 SARS-CoV and 2019 SARS-CoV-2 with the hACE2. Molecular docking and molecular dynamics simulations of the complexes and isolated proteins were performed, providing insights on their detailed pattern of interactions, and estimating the free energy of binding. The obtained results support previous studies indicating that the chemical affinity of the new SARS-CoV-2 for the hACE2 enzyme virus is much higher than the 2002 SARS-CoV. The herein calculated Gibbs free energy of binding to the hACE2 enzyme is, depending on the technique, from 5.11 kcal/mol to 8.39 kcal/mol more negative in the case of the new coronavirus’ RBD. In addition, within each employed technique, this free energy is consistently 61±2% stronger for SARS-CoV-2 than for SARS-CoV. This work presents a chemical reason for the difficulty in treating the SARS-CoV-2 virus using drugs targeting its Spike Protein, as well as helps to explain its infectivity, while defining a minimum free energy of binding for new drugs to be designed against this disease.<br></p>

scholarly journals Elucidation of the interactions between SARS-CoV-2 Spike protein and wild and mutant types of IFITM proteins by in silico methods

2021 ◽  
Author(s):  
Nazli Irmak Giritlioglu ◽  
Gizem Koprululu Kucuk
Keyword(s):  
Molecular Docking ◽  
Amino Acid ◽  
Binding Energy ◽  
Hydrogen Bonds ◽  
In Silico ◽  
Protein Complexes ◽  
Protein Product ◽  
Binding Energies ◽  
Spike Protein ◽  
Web Based

COVID-19 is a viral disease that has been a threat to the whole world since 2019. Although effective vaccines against the disease have been developed, there are still points to be clarified about the mechanism of SARS-CoV-2, which is the causative agent of COVID-19. In this study, we determined the binding energies and the bond types of complexes formed by open (6VYB) and closed (6VXX) forms of the Spike protein of SARS-CoV-2 and wild and mutant forms of IFITM1, IFITM2, and IFITM3 proteins using the molecular docking approach. First, all missense SNPs were found in the NCBI Single Nucleotide Polymorphism database (dbSNP) for IFITM1, IFITM2, and IFITM3 and analyzed with SIFT, PROVEAN, PolyPhen-2, SNAP2, Mutation Assessor, and PANTHER cSNP web-based tools to determine their pathogenicity. When at least four of these analysis tools showed that the SNP had a pathogenic effect on the protein product, this SNP was saved for further analysis. Delta delta G (DDG) and protein stability analysis for amino acid changes were performed in the web-based tools I-Mutant, MUpro, and SAAFEC-SEQ. The structural effect of amino acid change on the protein product was made using the HOPE web-based tool. HawkDock server was used for molecular docking and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) analysis and binding energies of all complexes were calculated. BIOVIA Discovery Studio program was utilized to visualize the complexes. Hydrogen bonds, salt bridges, and non-bonded contacts between Spike and IFITM protein chains in the complexes were detected with the PDBsum web-based tool. The best binding energy among the 6VYB-IFITM wild protein complexes belong to 6VYB-IFITM1 (-46.16 kcal/mol). Likewise, among the 6VXX-IFITM wild protein complexes, the most negative binding energy belongs to 6VXX-IFITM1 (-52.42 kcal/mol). An interesting result found in the study is the presence of hydrogen bonds between the cytoplasmic domain of the IFITM1 wild protein and the S2 domain of 6VYB. Among the Spike-IFITM mutant protein complexes, the best binding energy belongs to the 6VXX-IFITM2 N63S complex (-50.77 kcal/mol) and the worst binding energy belongs to the 6VXX-IFITM3 S50T complex (4.86 kcal/mol). The study suggests that IFITM1 protein may act as a receptor for SARS-CoV-2 Spike protein. Assays must be advanced from in silico to in vitro for the determination of the receptor-ligand interactions between IFITM proteins and SARS-CoV-2.

scholarly journals Deep Mutational Scanning of Dynamic Interaction Networks in the SARS-CoV-2 Spike Protein Complexes: Allosteric Hotspots Control Functional Mimicry and Resilience to Mutational Escape

2021 ◽  
Author(s):  
Gennady Verkhivker
Keyword(s):  
Protein Complexes ◽  
Signal Transmission ◽  
Specific Protein ◽  
Interaction Networks ◽  
Regulatory Control ◽  
Spike Protein ◽  
Global Network ◽  
Control Points ◽  
Residue Interaction ◽  
Allosteric Sites

We develop a computational approach for deep mutational scanning of residue interaction networks in the SARS-CoV-2 spike protein complexes to characterize mechanisms of functional mimicry and resilience to mutational escape by miniprotein inhibitors. Using a dynamic mutational profiling and sensitivity analysis of protein stability, binding interactions and global network parameters describing allosteric signaling, we identify regulatory hotspots in the SARS-CoV-2 S complexes with the ACE2 host receptor and ultra-potent miniproteins. The results revealed that global circulating variants are associated with allosteric control points that are dynamically coupled to structural stability hotspots. In this mechanism, variant-induced perturbations of flexible allosteric sites can result in global network changes and elicit specific protein responses. The binding affinity fingerprints and allosteric signatures of the SARS-CoV-2 complexes with miniproteins are determined by a dynamic cross-talk between regulatory control points and conformationally adaptable allosteric hotspots that collectively control structure-functional mimicry, signal transmission and resilience to mutational escape.

scholarly journals In Silico Evaluation of Different Flavonoids from Medicinal Plants for Their Potency against SARS-CoV-2

Biologics ◽  
2021 ◽  
Vol 1 (3) ◽  
pp. 416-434
Author(s):  
H. R. Abd El-Mageed ◽  
Doaa A. Abdelrheem ◽  
Md. Oliullah Rafi ◽  
Md. Takim Sarker ◽  
Khattab Al-Khafaji ◽  
...  
Keyword(s):  
Medicinal Plants ◽  
Binding Affinity ◽  
Active Sites ◽  
Protein Complexes ◽  
Biological Effects ◽  
Strong Stability ◽  
Md Simulations ◽  
Antiviral Drugs ◽  
Spike Protein ◽  
Global Threat

The ongoing pandemic situation of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a global threat to both the world economy and public health. Therefore, there is an urgent need to discover effective vaccines or drugs to fight against this virus. The flavonoids and their medicinal plant sources have already exhibited various biological effects, including antiviral, anti-inflammatory, antioxidant, etc. This study was designed to evaluate different flavonoids from medicinal plants as potential inhibitors against the spike protein (Sp) and main protease (Mpro) of SARS-CoV-2 using various computational approaches such as molecular docking, molecular dynamics. The binding affinity and inhibitory effects of all studied flavonoids were discussed and compared with some antiviral drugs that are currently being used in COVID-19 treatment namely favipiravir, lopinavir, and hydroxychloroquine, respectively. Among all studies flavonoids and proposed antiviral drugs, luteolin and mundulinol exhibited the highest binding affinity toward Mpro and Sp. Drug-likeness and ADMET studies revealed that the chosen flavonoids are safe and non-toxic. One hundred ns-MD simulations were implemented for luteolin-Mpro, mundulinol-Mpro, luteolin-Sp, and mundulinol-Sp complexes and the results revealed strong stability of these flavonoid-protein complexes. Furthermore, MM/PBSA confirms the stability of luteolin and mundulinol interactions within the active sites of this protein. In conclusion, our findings reveal that the promising activity of luteolin and mundulinol as inhibitors against COVID-19 via inhibiting the spike protein and major protease of SARS CoV-2, and we urge further research to achieve the clinical significance of our proposed molecular-based efficacy.

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