Computational design of ACE2-based short peptide inhibitors of SARS-CoV-2

Short Peptide ◽

Binding Domains ◽

<div>Peptide inhibitors against the SARS-CoV-2 coronavirus, currently causing a worldwide pandemic, are designed and simulated. The inhibitors are formed by two sequential self-supporting alpha-helices (bundle) extracted from the protease domain (PD) of angiotensin-converting enzyme 2 (ACE2), which binds to the SARS-CoV-2 receptor binding domains. Molecular dynamics simulations revealed that the peptides maintain their secondary structure and provide a highly specific and stable binding (blocking) to SARS-CoV-2, determined by their sequences and conformations. The proposed peptide inhibitors could provide simple therapeutics against the COVID-19 disease.</div>

Adaptive Evolution of Peptide Inhibitors for Mutating SARS-CoV-2

10.26434/chemrxiv.12622667 ◽

2020 ◽

Author(s):

Parth Chaturvedi ◽

Yanxiao Han ◽

Petr Kral ◽

Lela Vukovic

Keyword(s):

Adaptive Evolution ◽

Disease Outbreaks ◽

Global Scale ◽

Peptide Inhibitors ◽

Free Energies ◽

Binding Domains ◽

Protein Receptor ◽

Dynamics Simulations ◽

Computational Strategy

The SARS-CoV-2 virus is currently causing a worldwide pandemic with dramatic societal consequences for the humankind. In the last decades, disease outbreaks due to such zoonotic pathogens have appeared with an accelerated rate, which calls for an urgent development of<br>adaptive (smart) therapeutics. Here, we develop a computational strategy to adaptively evolve peptides that could selectively inhibit mutating S protein receptor binding domains (RBDs) of different SARS-CoV-2 viral strains from binding to their human host receptor, angiotensin-converting enzyme 2 (ACE2). Starting from suitable peptide templates, based on selected ACE2 segments (natural RBD binder), we gradually modify the templates by random mutations, while retaining those mutations that maximize their RBD-binding free energies. In this adaptive evolution, atomistic molecular dynamics simulations of the template-RBD complexes are iteratively perturbed by the peptide mutations, which are retained under favorable Monte Carlo decisions. The computational search will provide libraries<br>of optimized therapeutics capable of reducing the SARS-CoV-2 infection on a global scale. <br>

Computational analysis on the ACE2-derived peptides for neutralizing the ACE2 binding to the spike protein of SARS-CoV-2

10.1101/2020.05.03.075473 ◽

2020 ◽

Author(s):

Cecylia S. Lupala ◽

Vikash Kumar ◽

Xuanxuan Li ◽

Xiao-dong Su ◽

Haiguang Liu

Keyword(s):

Molecular Dynamics ◽

Severe Acute Respiratory Syndrome ◽

Computational Analysis ◽

Spike Protein ◽

Short Peptides ◽

Receptor Binding Domain ◽

Converting Enzyme ◽

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.

Curious Binding Energy Increase between the Receptor-Binding Domain of the SARS-CoV-2 Spike Protein and Angiotensin-Converting Enzyme 2 Adsorbed on a Silane Monolayer from Molecular Dynamics Simulations

The Journal of Physical Chemistry B ◽

10.1021/acs.jpcb.1c06050 ◽

2021 ◽

Author(s):

Solène Lecot ◽

Yann Chevolot ◽

Magali Phaner-Goutorbe ◽

Christelle Yeromonahos

Keyword(s):

Molecular Dynamics ◽

Binding Energy ◽

Receptor Binding ◽

Spike Protein ◽

Receptor Binding Domain ◽

Converting Enzyme ◽

Energy Increase ◽

Adaptive Evolution of Peptide Inhibitors for Mutating SARS-CoV-2

10.26434/chemrxiv.12622667.v1 ◽

2020 ◽

Author(s):

Lela Vukovic ◽

Yanxiao Han ◽

Parth Chaturvedi ◽

Petr Kral

Keyword(s):

Adaptive Evolution ◽

Disease Outbreaks ◽

Global Scale ◽

Peptide Inhibitors ◽

Free Energies ◽

Binding Domains ◽

Protein Receptor ◽

Dynamics Simulations ◽

Computational Strategy

The SARS-CoV-2 virus is currently causing a worldwide pandemic with dramatic societal consequences for the humankind. In the last decades, disease outbreaks due to such zoonotic pathogens have appeared with an accelerated rate, which calls for an urgent development of<br>adaptive (smart) therapeutics. Here, we develop a computational strategy to adaptively evolve peptides that could selectively inhibit mutating S protein receptor binding domains (RBDs) of different SARS-CoV-2 viral strains from binding to their human host receptor, angiotensin-converting enzyme 2 (ACE2). Starting from suitable peptide templates, based on selected ACE2 segments (natural RBD binder), we gradually modify the templates by random mutations, while retaining those mutations that maximize their RBD-binding free energies. In this adaptive evolution, atomistic molecular dynamics simulations of the template-RBD complexes are iteratively perturbed by the peptide mutations, which are retained under favorable Monte Carlo decisions. The computational search will provide libraries<br>of optimized therapeutics capable of reducing the SARS-CoV-2 infection on a global scale. <br>

Molecular Dynamics Simulation Study of the Interaction between Human Angiotensin Converting Enzyme 2 and Spike Protein Receptor Binding Domain of the SARS-CoV-2 B.1.617 Variant

Biomolecules ◽

10.3390/biom11081244 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1244

Author(s):

Priya Antony ◽

Ranjit Vijayan

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Receptor Binding ◽

Binding Domain ◽

Receptor Binding Domain ◽

Converting Enzyme ◽

S Protein ◽

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has had a significant impact on people’s daily lives. The rapidly spreading B.1.617 lineage harbors two key mutations—L452R and E484Q—in the receptor binding domain (RBD) of its spike (S) protein. To understand the impact and structural dynamics of the variations in the interface of S protein and its host factor, the human angiotensin-converting enzyme 2 (hACE2), triplicate 500 ns molecular dynamics simulations were performed using single (E484Q or L452R) and double (E484Q + L452R) mutant structures and compared to wild type simulations. Our results indicate that the E484Q mutation disrupts the conserved salt bridge formed between Lys31 of hACE2 and Glu484 of S protein. Additionally, E484Q, which could favor the up conformation of the RBD, may help in enhanced hACE2 binding and immune escape. L452R introduces a charged patch near the binding surface that permits increased electrostatic attraction between the proteins. An improved network of intramolecular interactions observed is likely to increase the stability of the S protein and conformational changes may prevent the binding of neutralizing antibodies. The results obtained from the molecular dynamics simulations suggest that structural and dynamic changes introduced by these variations enhance the affinity of the viral S protein to hACE2 and could form the basis for further studies.

The Conformation and Assignment of the Proton NMR Spectrum in Water of DX600, a Bioactive Peptide with a Random Coil Conformation

International Journal of Spectroscopy ◽

10.1155/2011/296256 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Wayne E. Steinmetz ◽

Timothy N. Carrell ◽

Richard B. Peprah

Keyword(s):

Molecular Dynamics ◽

Selective Inhibitor ◽

Random Coil ◽

Proton Spectrum ◽

Converting Enzyme ◽

Small Peptide ◽

Nmr Spectrum ◽

Nmr Methods ◽

DX600, a small peptide with 26 residues, is a potent, highly selective inhibitor of angiotensin converting enzyme 2 (ACE2). A range of NMR methods including TOCSY and ROESY yield an assignment of its proton spectrum in water and constraints on its conformation. Constrained molecular dynamics simulations of solvated DX600 show that the peptide's most abundant conformer adopts a predominantly random coil conformation. Constrained by the disulfide bond, its backbone defines an overhand knot with frayed ends.

Adaptive Evolution of Peptide Inhibitors for Mutating SARS-CoV-2

10.26434/chemrxiv.12622667.v2 ◽

2020 ◽

Author(s):

Parth Chaturvedi ◽

Yanxiao Han ◽

Petr Kral ◽

Lela Vukovic

Keyword(s):

Adaptive Evolution ◽

Disease Outbreaks ◽

Global Scale ◽

Peptide Inhibitors ◽

Free Energies ◽

Binding Domains ◽

Protein Receptor ◽

Dynamics Simulations ◽

Computational Strategy

The SARS-CoV-2 virus is currently causing a worldwide pandemic with dramatic societal consequences for the humankind. In the last decades, disease outbreaks due to such zoonotic pathogens have appeared with an accelerated rate, which calls for an urgent development of<br>adaptive (smart) therapeutics. Here, we develop a computational strategy to adaptively evolve peptides that could selectively inhibit mutating S protein receptor binding domains (RBDs) of different SARS-CoV-2 viral strains from binding to their human host receptor, angiotensin-converting enzyme 2 (ACE2). Starting from suitable peptide templates, based on selected ACE2 segments (natural RBD binder), we gradually modify the templates by random mutations, while retaining those mutations that maximize their RBD-binding free energies. In this adaptive evolution, atomistic molecular dynamics simulations of the template-RBD complexes are iteratively perturbed by the peptide mutations, which are retained under favorable Monte Carlo decisions. The computational search will provide libraries<br>of optimized therapeutics capable of reducing the SARS-CoV-2 infection on a global scale. <br>

ACE2 fragment as a decoy for novel SARS-Cov-2 virus

10.1101/2020.04.06.028647 ◽

2020 ◽

Cited By ~ 1

Author(s):

Fabiana Renzi ◽

Dario Ghersi

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Cellular Membrane ◽

Converting Enzyme ◽

S Protein ◽

Viral Binding ◽

Binding Surface ◽

Novel SARS-Cov-2 enters human cells via interaction between the surface spike (S) glycoprotein and the cellular membrane receptor angiotensin-converting enzyme 2 (ACE2). Using a combination of comparative structural analyses of the binding surface of the S protein to ACE2, docking experiments, and molecular dynamics simulations we computationally identified a minimal, stable fragment of ACE2. This fragment binds to the S protein, is soluble, and appears not to bind to the physiological ligand angiotensinII. These results suggest a possible use of the ACE2 fragment as a decoy that could interfere with viral binding by competition.

Computational Design of Macrocyclic Binders of S100B(ββ): Novel Peptide Theranostics

Molecules ◽

10.3390/molecules26030721 ◽

2021 ◽

Vol 26 (3) ◽

pp. 721

Author(s):

Srinivasaraghavan Kannan ◽

Pietro G. A. Aronica ◽

Thanh Binh Nguyen ◽

Jianguo Li ◽

Chandra S. Verma

Keyword(s):

Molecular Dynamics ◽

Computational Design ◽

Diagnostic Tools ◽

Stapled Peptides ◽

Altered Expression ◽

Cellular Processes ◽

High Affinity ◽

Limited Success ◽

Dynamics Simulations ◽

Partner Proteins

S100B(ββ) proteins are a family of multifunctional proteins that are present in several tissues and regulate a wide variety of cellular processes. Their altered expression levels have been associated with several human diseases, such as cancer, inflammatory disorders and neurodegenerative conditions, and hence are of interest as a therapeutic target and a biomarker. Small molecule inhibitors of S100B(ββ) have achieved limited success. Guided by the wealth of available experimental structures of S100B(ββ) in complex with diverse peptides from various protein interacting partners, we combine comparative structural analysis and molecular dynamics simulations to design a series of peptides and their analogues (stapled) as S100B(ββ) binders. The stapled peptides were subject to in silico mutagenesis experiments, resulting in optimized analogues that are predicted to bind to S100B(ββ) with high affinity, and were also modified with imaging agents to serve as diagnostic tools. These stapled peptides can serve as theranostics, which can be used to not only diagnose the levels of S100B(ββ) but also to disrupt the interactions of S100B(ββ) with partner proteins which drive disease progression, thus serving as novel therapeutics.