scholarly journals Predicting the Potential Effect of E484K Mutation on the Binding of 28 Antibodies to the Spike Protein of SARS-CoV-2 by Molecular Dynamics Simulation and Free Energy Calculation

2021 ◽  
Author(s):  
Leyun Wu ◽  
Cheng Peng ◽  
Zhijian Xu ◽  
weiliang zhu
Keyword(s):  
Free Energy ◽  
Binding Affinity ◽  
Immune Escape ◽  
Binding Free Energy ◽  
Experimental Studies ◽  
Potential Effect ◽  
Dynamics Simulation ◽  
Spike Protein ◽  
Energy Calculation ◽  
Potential Impact

Vaccines and antibody therapeutic are needed to fight the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has spread since 2020. Experimental studies have shown that the E484K variant may escape the neutralization of antibodies. To explore the potential impact of E484K mutation on the antibody binding affinity, we calculated the binding free energy of 28 antibodies to the wild type and K484 mutant of the spike protein of SARS-CoV-2. We found that 71% of the antibodies show lower binding affinity to the E484K mutant, indicating the highly possible immune escape risk of the mutated virus. Further analysis revealed that the other mutations, e.g. F490 and V483, are also likely to cause immune escape.

scholarly journals Predicting the Potential Effect of E484K Mutation on the Binding of 28 Antibodies to the Spike Protein of SARS-CoV-2 by Molecular Dynamics Simulation and Free Energy Calculation

2021 ◽  
Author(s):  
Leyun Wu ◽  
Cheng Peng ◽  
Zhijian Xu ◽  
weiliang zhu
Keyword(s):  
Free Energy ◽  
Binding Affinity ◽  
Immune Escape ◽  
Binding Free Energy ◽  
Experimental Studies ◽  
Potential Effect ◽  
Dynamics Simulation ◽  
Spike Protein ◽  
Energy Calculation ◽  
Potential Impact

Vaccines and antibody therapeutic are needed to fight the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has spread since 2020. Experimental studies have shown that the E484K variant may escape the neutralization of antibodies. To explore the potential impact of E484K mutation on the antibody binding affinity, we calculated the binding free energy of 28 antibodies to the wild type and K484 mutant of the spike protein of SARS-CoV-2. We found that 71% of the antibodies show lower binding affinity to the E484K mutant, indicating the highly possible immune escape risk of the mutated virus. Further analysis revealed that the other mutations, e.g. F490 and V483, are also likely to cause immune escape.

scholarly journals Molecular simulation of SARS-CoV-2 spike protein binding to pangolin ACE2 or human ACE2 natural variants reveals altered susceptibility to infection

2020 ◽  
Vol 101 (9) ◽  
pp. 921-924 ◽  
Author(s):  
Jingfang Wang ◽  
Xintian Xu ◽  
Xinbo Zhou ◽  
Ping Chen ◽  
Huiying Liang ◽  
...  
Keyword(s):  
Free Energy ◽  
Protein Binding ◽  
Binding Affinity ◽  
Binding Free Energy ◽  
Virus Transmission ◽  
Dynamics Simulation ◽  
Spike Protein ◽  
Susceptibility To Infection ◽  
Natural Variants ◽  
Complex Models

We constructed complex models of SARS-CoV-2 spike protein binding to pangolin or human ACE2, the receptor for virus transmission, and estimated the binding free energy changes using molecular dynamics simulation. SARS-CoV-2 can bind to both pangolin and human ACE2, but has a significantly lower binding affinity for pangolin ACE2 due to the increased binding free energy (9.5 kcal mol−1). Human ACE2 is among the most polymorphous genes, for which we identified 317 missense single-nucleotide variations (SNVs) from the dbSNP database. Three SNVs, E329G (rs143936283), M82I (rs267606406) and K26R (rs4646116), had a significant reduction in binding free energy, which indicated higher binding affinity than wild-type ACE2 and greater susceptibility to SARS-CoV-2 infection for people with them. Three other SNVs, D355N (rs961360700), E37K (rs146676783) and I21T (rs1244687367), had a significant increase in binding free energy, which indicated lower binding affinity and reduced susceptibility to SARS-CoV-2 infection.

scholarly journals Phytochemical Moieties From Indian Traditional Medicine for Targeting Dual Hotspots on SARS-CoV-2 Spike Protein: An Integrative in-silico Approach

2021 ◽  
Vol 8 ◽  
Author(s):  
V. Umashankar ◽  
Sanjay H. Deshpande ◽  
Harsha V. Hegde ◽  
Ishwar Singh ◽  
Debprasad Chattopadhyay
Keyword(s):  
Free Energy ◽  
Binding Energy ◽  
Traditional Medicine ◽  
Binding Affinity ◽  
In Silico ◽  
Binding Free Energy ◽  
Contemporary Literature ◽  
Dynamics Simulation ◽  
Spike Protein ◽  
Syzygium Aromaticum

SARS-CoV-2 infection across the world has led to immense turbulence in the treatment modality, thus demanding a swift drug discovery process. Spike protein of SARS-CoV-2 binds to ACE2 receptor of human to initiate host invasion. Plethora of studies demonstrate the inhibition of Spike-ACE2 interactions to impair infection. The ancient Indian traditional medicine has been of great interest of Virologists worldwide to decipher potential antivirals. Hence, in this study, phytochemicals (1,952 compounds) from eight potential medicinal plants used in Indian traditional medicine were meticulously collated, based on their usage in respiratory disorders, along with immunomodulatory and anti-viral potential from contemporary literature. Further, these compounds were virtually screened against Receptor Binding Domain (RBD) of Spike protein. The potential compounds from each plant were prioritized based on the binding affinity, key hotspot interactions at ACE2 binding region and glycosylation sites. Finally, the potential hits in complex with spike protein were subjected to Molecular Dynamics simulation (450 ns), to infer the stability of complex formation. Among the compounds screened, Tellimagrandin-II (binding energy of −8.2 kcal/mol and binding free energy of −32.08 kcal/mol) from Syzygium aromaticum L. and O-Demethyl-demethoxy-curcumin (binding energy of −8.0 kcal/mol and binding free energy of −12.48 kcal/mol) from Curcuma longa L. were found to be highly potential due to their higher binding affinity and significant binding free energy (MM-PBSA), along with favorable ADMET properties and stable intermolecular interactions with hotspots (including the ASN343 glycosylation site). The proposed hits are highly promising, as these are resultant of stringent in silico checkpoints, traditionally used, and are documented through contemporary literature. Hence, could serve as promising leads for subsequent experimental validations.

Current Trends in Docking Methodologies

Oncology ◽  
2017 ◽  
pp. 829-847
Author(s):  
Shubhandra Tripathi ◽  
Akhil Kumar ◽  
Amandeep Kaur Kahlon ◽  
Ashok Sharma
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Binding Affinity ◽  
Binding Free Energy ◽  
Energy Calculation ◽  
Molecular Binding ◽  
New Horizons ◽  
Current Trends ◽  
Complex Scheme ◽  
Dynamics Simulations

Molecular docking was earlier considered to predict the binding affinity of the receptor and ligand molecules. With the progress in computational power and developing approaches, new horizons are now opening for accurate prediction of molecular binding affinity. In the current book chapter, recent strategies for Computer-Aided Drug Designing (CADD) including virtual screening and molecular docking, encompassing molecular dynamics simulations, and binding free energy calculation methods are discussed. Brief overview of different binding free energy methods MMPBSA, MMGBSA, LIE and TI have also been given along with the recent Relaxed Complex Scheme protocol.

scholarly journals Hydrogen Bond Stability of Quinazoline Derivatives Compounds in Complex against EGFR using Molecular Dynamics Simulation

2019 ◽  
Vol 19 (2) ◽  
pp. 461
Author(s):  
Herlina Rasyid ◽  
Bambang Purwono ◽  
Thomas S Hofer ◽  
Harno Dwi Pranowo
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bond ◽  
Free Energy ◽  
Molecular Dynamics Simulation ◽  
Binding Free Energy ◽  
Dynamics Simulation ◽  
Inhibition Mechanism ◽  
Energy Calculation ◽  
Protein Receptor ◽  
The Stability

Lung cancer was a second common cancer case due to the high cigarette smoking activity both in men and women. One of protein receptor which plays an important role in the growth of the tumor is Epidermal Growth Factor Receptor (EGFR). EGFR protein is the most frequent protein mutation in cancer and promising target to inhibit the cancer growth. In this work, the stability of the hydrogen bond as the main interaction in the inhibition mechanism of cancer will be evaluated using molecular dynamics simulation. There were two compounds (A1 and A2) as new potential inhibitors that were complexed against the EGFR protein. The dynamic properties of each complexed were compared with respect to erlotinib against EGFR. The result revealed that both compounds had an interaction in the main catalytic area of protein receptor which is at methionine residue. Inhibitor A1 showed additional interactions during simulation time but the interactions tend to be weak. Inhibitor A2 displayed a more stable interaction. Following dynamics simulation, binding free energy calculation was performed by two scoring techniques MM/GB(PB)SA method and gave a good correlation with the stability of the complex. Furthermore, potential inhibitor A2 had a lower binding free energy as a direct consequence of the stability of hydrogen bond interaction.

scholarly journals An Effective MM/GBSA Protocol for Absolute Binding Free Energy Calculations: A Case Study on SARS-CoV-2 Spike Protein and the Human ACE2 Receptor

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2383
Author(s):  
Negin Forouzesh ◽  
Nikita Mishra
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Normal Mode Analysis ◽  
Free Energy Calculations ◽  
Spike Protein ◽  
Upper And Lower Bounds ◽  
Mode Analysis ◽  
Implicit Solvent ◽  
Energy Calculation ◽  
Generalized Born

The binding free energy calculation of protein–ligand complexes is necessary for research into virus–host interactions and the relevant applications in drug discovery. However, many current computational methods of such calculations are either inefficient or inaccurate in practice. Utilizing implicit solvent models in the molecular mechanics generalized Born surface area (MM/GBSA) framework allows for efficient calculations without significant loss of accuracy. Here, GBNSR6, a new flavor of the generalized Born model, is employed in the MM/GBSA framework for measuring the binding affinity between SARS-CoV-2 spike protein and the human ACE2 receptor. A computational protocol is developed based on the widely studied Ras–Raf complex, which has similar binding free energy to SARS-CoV-2/ACE2. Two options for representing the dielectric boundary of the complexes are evaluated: one based on the standard Bondi radii and the other based on a newly developed set of atomic radii (OPT1), optimized specifically for protein–ligand binding. Predictions based on the two radii sets provide upper and lower bounds on the experimental references: −14.7(ΔGbindBondi)<−10.6(ΔGbindExp.)<−4.1(ΔGbindOPT1) kcal/mol. The consensus estimates of the two bounds show quantitative agreement with the experiment values. This work also presents a novel truncation method and computational strategies for efficient entropy calculations with normal mode analysis. Interestingly, it is observed that a significant decrease in the number of snapshots does not affect the accuracy of entropy calculation, while it does lower computation time appreciably. The proposed MM/GBSA protocol can be used to study the binding mechanism of new variants of SARS-CoV-2, as well as other relevant structures.

scholarly journals Computational Insights into the Binding Mechanism of OxyS sRNA with Chaperone Protein Hfq

Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1653
Author(s):  
Mengxin Li ◽  
Yalong Cong ◽  
Yifei Qi ◽  
John Z. H. Zhang
Keyword(s):  
Gene Expression ◽  
Free Energy ◽  
Binding Affinity ◽  
Binding Free Energy ◽  
Complex Structure ◽  
Experimental Studies ◽  
Experimental Result ◽  
Regulatory Function ◽  
Binding Mechanism ◽  
Chaperone Protein

Under the oxidative stress condition, the small RNA (sRNA) OxyS that acts as essential post-transcriptional regulators of gene expression is produced and plays a regulatory function with the assistance of the RNA chaperone Hfq protein. Interestingly, experimental studies found that the N48A mutation of Hfq protein could enhance the binding affinity with OxyS while resulting in the defection of gene regulation. However, how the Hfq protein interacts with sRNA OxyS and the origin of the stronger affinity of N48A mutation are both unclear. In this paper, molecular dynamics (MD) simulations were performed on the complex structure of Hfq and OxyS to explore their binding mechanism. The molecular mechanics generalized born surface area (MM/GBSA) and interaction entropy (IE) method were combined to calculate the binding free energy between Hfq and OxyS sRNA, and the computational result was correlated with the experimental result. Per-residue decomposition of the binding free energy revealed that the enhanced binding ability of the N48A mutation mainly came from the increased van der Waals interactions (vdW). This research explored the binding mechanism between Oxys and chaperone protein Hfq and revealed the origin of the strong binding affinity of N48A mutation. The results provided important insights into the mechanism of gene expression regulation affected by protein mutations.

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