Evaluation of the Binding Mechanism of Human Defensin 5 in a Bacterial Membrane: A Simulation Study

Human α-defensin 5 (HD5) is a host-defense peptide exhibiting broad-spectrum antimicrobial activity. The lipopolysaccharide (LPS) layer on the Gram-negative bacterial membrane acts as a barrier to HD5 insertion. Therefore, the pore formation and binding mechanism remain unclear. Here, the binding mechanisms at five positions along the bacterial membrane axis were investigated using Molecular Dynamics. (MD) simulations. We found that HD5 initially placed at positions 1 to 3 moved up to the surface, while HD5 positioned at 4 and 5 remained within the membrane interacting with the middle and inner leaflet of the membrane, respectively. The arginines were key components for tighter binding with 3-deoxy-d-manno-octulosonic acid (KDO), phosphates of the outer and inner leaflets. KDO appeared to retard the HD5 penetration.

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A boosted unbiased molecular dynamics method for predicting ligands binding mechanisms: probing the binding pathway of dasatinib to Src-kinase

Bioinformatics ◽

10.1093/bioinformatics/btaa565 ◽

2020 ◽

Vol 36 (18) ◽

pp. 4714-4720

Author(s):

Farzin Sohraby ◽

Mostafa Javaheri Moghadam ◽

Masoud Aliyar ◽

Hassan Aryapour

Keyword(s):

Molecular Dynamics ◽

Ligand Binding ◽

Md Simulation ◽

Src Kinase ◽

Deep Understanding ◽

Md Simulations ◽

Binding Mode ◽

Supplementary Information ◽

Computational Resources ◽

Binding Mechanisms

Abstract Summary Small molecules such as metabolites and drugs play essential roles in biological processes and pharmaceutical industry. Knowing their interactions with biomacromolecular targets demands a deep understanding of binding mechanisms. Dozens of papers have suggested that discovering of the binding event by means of conventional unbiased molecular dynamics (MD) simulation urges considerable amount of computational resources, therefore, only one who holds a cluster or a supercomputer can afford such extensive simulations. Thus, many researchers who do not own such resources are reluctant to take the benefits of running unbiased MD simulation, in full atomistic details, when studying a ligand binding pathway. Many researchers are impelled to be content with biased MD simulations which seek its validation due to its intrinsic preconceived framework. In this work, we have presented a workable stratagem to encourage everyone to perform unbiased (unguided) MD simulations, in this case a protein–ligand binding process, by typical desktop computers and so achieve valuable results in nanosecond time scale. Here, we have described a dynamical binding’s process of an anticancer drug, the dasatinib, to the c-Src kinase in full atomistic details for the first time, without applying any biasing force or potential which may lead the drug to artificial interactions with the protein. We have attained multiple independent binding events which occurred in the nanosecond time scales, surprisingly as little as ∼30 ns. Both the protonated and deprotonated forms of the dasatinib reached the crystallographic binding mode without having any major intermediate state during induction. Availability and implementation The links of the tutorial and technical documents are accessible in the article. Supplementary information Supplementary data are available at Bioinformatics online.

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Evaluation of Host Defense Peptide (CaD23)-Antibiotic Interaction and Mechanism of Action: Insights from Experimental and Molecular Dynamics Simulations Studies

10.1101/2021.06.26.450050 ◽

2021 ◽

Author(s):

Darren S J Ting ◽

Jianguo Li ◽

Chandra Shekhar Verma ◽

Eunice T L Goh ◽

Mario Nubile ◽

...

Keyword(s):

Molecular Dynamics ◽

Host Defense ◽

Mechanism Of Action ◽

Inhibitory Concentration ◽

Md Simulations ◽

Antimicrobial Action ◽

Antimicrobial Efficacy ◽

Sytox Green ◽

Broth Microdilution Method ◽

Uptake Assay

Background/aim: Host defense peptides (HDPs) have the potential to provide a novel solution to antimicrobial resistance (AMR) in view of their unique and broad-spectrum antimicrobial activities. We had recently developed a novel hybrid HDP based on LL-37 and human beta-defensin-2, named CaD23, which was shown to exhibit good in vivo antimicrobial efficacy against Staphylococcus aureus in a bacterial keratitis murine model. This study aimed to examine the potential CaD23-antibiotic synergism and to evaluate the underlying mechanism of action of CaD23. Methods: Antimicrobial efficacy was determined using minimum inhibitory concentration (MIC) assay with broth microdilution method. Peptide-antibiotic interaction was evaluated against S. aureus, methicillin-resistant S. aureus (MRSA), and Pseudomonas aeruginosa using established checkerboard assay and time-kill kinetics assay. Fractional inhibitory concentration index (FICI) was calculated and interpreted as synergistic (FICI<0.5), additive (FICI between 0.5-1.0), indifferent (FICI between >1.0 and </=4), or antagonistic (FICI>4). SYTOX green uptake assay was performed to determine the membrane-permeabilising action of CaD23. Molecular dynamics (MD) simulations were performed to evaluate the interaction of CaD23 with bacterial and mammalian mimetic membranes. Results: CaD23-amikacin and CaD23-levofloxacin combination treatment exhibited a strong additive effect against S. aureus SH1000 (FICI=0.56) and MRSA43300 (FICI=0.56) but a borderline additive-to-indifferent effect against P. aeruginosa (FIC=1.0-2.0). CaD23 (at 25 ug/ml; 2x MIC) was able to achieve complete killing of S. aureus within 30 mins. When used at sub-MIC concentration (3.1 ug/ml; 0.25x MIC), it was able to expedite the antimicrobial action of amikacin against S. aureus by 50%. The rapid antimicrobial action of CaD23 was attributed to the underlying membrane-permeabilising mechanism of action, evidenced by the SYTOX green uptake assay and MD simulations studies. MD simulations revealed that cationicity, alpha-helicity, amphiphilicity and hydrophobicity (related to the Trp residue at C-terminal) play important roles in the antimicrobial action of CaD23. Conclusions: CaD23 is a novel membrane-active synthetic HDP that can enhance and expedite the antimicrobial action of antibiotics against Gram-positive bacteria when used in combination. MD simulation serves as a useful tool in dissecting the mechanism of action and guiding the design and optimisation of HDPs.

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Interactions of aminoglycoside antibiotics with rRNA

Biochemical Society Transactions ◽

10.1042/bst20160087 ◽

2016 ◽

Vol 44 (4) ◽

pp. 987-993 ◽

Cited By ~ 6

Author(s):

Joanna Trylska ◽

Marta Kulik

Keyword(s):

Molecular Dynamics ◽

Ribosomal Subunit ◽

Md Simulations ◽

Aminoglycoside Antibiotics ◽

Computational Studies ◽

Gram Negative Bacteria ◽

Protein Synthesis Inhibitors ◽

Gram Negative ◽

Adverse Side Effects ◽

16S Rna

Aminoglycoside antibiotics are protein synthesis inhibitors applied to treat infections caused mainly by aerobic Gram-negative bacteria. Due to their adverse side effects they are last resort antibiotics typically used to combat pathogens resistant to other drugs. Aminoglycosides target ribosomes. We describe the interactions of aminoglycoside antibiotics containing a 2-deoxystreptamine (2-DOS) ring with 16S rRNA. We review the computational studies, with a focus on molecular dynamics (MD) simulations performed on RNA models mimicking the 2-DOS aminoglycoside binding site in the small ribosomal subunit. We also briefly discuss thermodynamics of interactions of these aminoglycosides with their 16S RNA target.

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A Potent Host Defense Peptide Triggers DNA Damage and Is Active against Multidrug-Resistant Gram-Negative Pathogens

ACS Infectious Diseases ◽

10.1021/acsinfecdis.0c00051 ◽

2020 ◽

Vol 6 (5) ◽

pp. 1250-1263 ◽

Cited By ~ 1

Author(s):

Samuel A. Juliano ◽

Leonardo F. Serafim ◽

Searle S. Duay ◽

Maria Heredia Chavez ◽

Gaurav Sharma ◽

...

Keyword(s):

Dna Damage ◽

Host Defense ◽

Multidrug Resistant ◽

Gram Negative ◽

Host Defense Peptide

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Coarse-grained molecular dynamics simulations of nanoplastics interacting with a hydrophobic environment in aqueous solution

RSC Advances ◽

10.1039/d1ra04439g ◽

2021 ◽

Vol 11 (44) ◽

pp. 27734-27744

Author(s):

Lorenz F. Dettmann ◽

Oliver Kühn ◽

Ashour A. Ahmed

Keyword(s):

Carbon Nanotubes ◽

Molecular Dynamics ◽

Aqueous Solution ◽

Water Treatment ◽

Md Simulations ◽

Coarse Grained ◽

Treatment Technologies ◽

Dynamics Simulations ◽

Binding Mechanisms ◽

Soil And Water

The binding mechanisms of nanoplastics (NPs) to carbon nanotubes as hydrophobic environmental systems have been explored by coarse-grained MD simulations. The results could be closely connected to fate of NPs in soil and water treatment technologies.

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Binding mechanism of neutralizing Nanobodies targeting SARS-CoV-2 Spike Glycoprotein

10.1101/2021.04.23.441186 ◽

2021 ◽

Author(s):

Mert Golcuk ◽

Aysima Hacisuleyman ◽

Burak Erman ◽

Ahmet Yildiz ◽

Mert Gur

Keyword(s):

Molecular Dynamics ◽

Severe Acute Respiratory Syndrome ◽

Binding Site ◽

Receptor Binding ◽

Md Simulations ◽

Underlying Mechanism ◽

Electrostatic Repulsion ◽

Receptor Binding Domain ◽

Binding Mechanism ◽

Pairwise Interactions

ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters human cells upon binding of its spike (S) glycoproteins to ACE2 receptors. Several nanobodies neutralize SARS-CoV-2 infection by binding to the receptor-binding domain (RBD) of S protein, but the underlying mechanism is not well understood. Here, we identified an extended network of pairwise interactions between RBD and nanobodies H11-H4, H11-D4, and Ty1 by performing all-atom molecular dynamics (MD) simulations. Simulations of the nanobody-RBD-ACE2 complex revealed that H11-H4 more strongly binds to RBD without overlapping with ACE2 and triggers dissociation of ACE2 due to electrostatic repulsion. In comparison, Ty1 binding results in dissociation of ACE2 from RBD due to an overlap with the ACE2 binding site, whereas H11-D4 binding does not trigger ACE2 dissociation. Mutations in SARS-CoV-2 501Y.V1 and 501.V2 variants resulted in a negligible effect on RBD-ACE2 binding. However, the 501.V2 variant weakened H11-H4 and H11-D4 binding while strengthening Ty1 binding to RBD. Our simulations indicate that all three nanobodies can neutralize 501Y.V1 while Ty1 is more effective against the 501.V2 variant.

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Correction to “A Potent Host Defense Peptide Triggers DNA Damage and Is Active against Multidrug-Resistant Gram-Negative Pathogens”

ACS Infectious Diseases ◽

10.1021/acsinfecdis.0c00549 ◽

2020 ◽

Vol 6 (9) ◽

pp. 2542-2542

Author(s):

Samuel A. Juliano ◽

Leonardo F. Serafim ◽

Searle S. Duay ◽

Maria Heredia Chavez ◽

Gaurav Sharma ◽

...

Keyword(s):

Dna Damage ◽

Host Defense ◽

Multidrug Resistant ◽

Gram Negative ◽

Host Defense Peptide

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Molecular Dynamics Simulations of the Host Defense Peptide Temporin L and Its Q3K Derivative: An Atomic Level View from Aggregation in Water to Bilayer Perturbation

Molecules ◽

10.3390/molecules22071235 ◽

2017 ◽

Vol 22 (7) ◽

pp. 1235 ◽

Cited By ~ 6

Author(s):

Andrea Farrotti ◽

Paolo Conflitti ◽

Saurabh Srivastava ◽

Jimut Ghosh ◽

Antonio Palleschi ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Host Defense ◽

Atomic Level ◽

Host Defense Peptide ◽

Dynamics Simulations

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Evaluation of Host Defense Peptide (CaD23)-Antibiotic Interaction and Mechanism of Action: Insights From Experimental and Molecular Dynamics Simulations Studies

Frontiers in Pharmacology ◽

10.3389/fphar.2021.731499 ◽

2021 ◽

Vol 12 ◽

Author(s):

Darren Shu Jeng Ting ◽

Jianguo Li ◽

Chandra S. Verma ◽

Eunice T. L. Goh ◽

Mario Nubile ◽

...

Keyword(s):

Molecular Dynamics ◽

Secondary Structure ◽

Host Defense ◽

Mechanism Of Action ◽

Md Simulations ◽

Secondary Structures ◽

Cd Spectroscopy ◽

Antimicrobial Action ◽

Sytox Green ◽

Uptake Assay

Background/Aim: Host defense peptides (HDPs) have the potential to provide a novel solution to antimicrobial resistance (AMR) in view of their unique and broad-spectrum antimicrobial activities. We had recently developed a novel hybrid HDP based on LL-37 and human beta-defensin-2, named CaD23, which was shown to exhibit good in vivo antimicrobial efficacy against Staphylococcus aureus in a bacterial keratitis murine model. This study aimed to examine the potential CaD23-antibiotic synergism and the secondary structure and underlying mechanism of action of CaD23.Methods: Peptide-antibiotic interaction was evaluated against S. aureus, methicillin-resistant S. aureus (MRSA), and Pseudomonas aeruginosa using established checkerboard and time-kill assays. Fractional inhibitory concentration index (FICI) was calculated and interpreted as synergistic (FIC<0.5), additive (FIC between 0.5–1.0), indifferent (FIC between >1.0 and ≤4), or antagonistic (FIC>4). SYTOX green uptake assay was performed to determine the membrane-permeabilising action of CaD23. Molecular dynamics (MD) simulations were performed to evaluate the interaction of CaD23 with bacterial and mammalian mimetic membranes. Circular dichroism (CD) spectroscopy was also performed to examine the secondary structures of CaD23.Results: CaD23-amikacin and CaD23-levofloxacin combination treatment exhibited a strong additive effect against S. aureus SH1000 (FICI = 0.60–0.69) and MRSA43300 (FICI = 0.56–0.60) but an indifferent effect against P. aeruginosa (FIC = 1.03–1.15). CaD23 (at 25 μg/ml; 2xMIC) completely killed S. aureus within 30 min. When used at sub-MIC concentration (3.1 μg/ml; 0.25xMIC), it was able to expedite the antimicrobial action of amikacin against S. aureus by 50%. The rapid antimicrobial action of CaD23 was attributed to the underlying membrane-permeabilising mechanism of action, evidenced by the SYTOX green uptake assay and MD simulations studies. MD simulations revealed that cationicity, alpha-helicity, amphiphilicity and hydrophobicity (related to the Trp residue at C-terminal) play important roles in the antimicrobial action of CaD23. The secondary structures of CaD23 observed in MD simulations were validated by CD spectroscopy.Conclusion: CaD23 is a novel alpha-helical, membrane-active synthetic HDP that can enhance and expedite the antimicrobial action of antibiotics against Gram-positive bacteria when used in combination. MD simulations serves as a powerful tool in revealing the peptide secondary structure, dissecting the mechanism of action, and guiding the design and optimisation of HDPs.

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