Towards designing globular antimicrobial peptide mimics: role of polar functional groups in biomimetic ternary antimicrobial polymers

Mapping Intimacies ◽

10.1101/2020.10.24.353243 ◽

2020 ◽

Author(s):

Garima Rani ◽

Kenichi Kuroda ◽

Satyavani Vemparala

Keyword(s):

Antimicrobial Polymers ◽

Bacterial Membranes ◽

Structure Lipid ◽

Polar Groups ◽

Polymer Aggregates ◽

Methacrylate Polymers ◽

Dynamics Simulations ◽

Polar Functional Groups ◽

Ternary Polymer

Using atomistic molecular dynamics simulations, we study the interaction of ternary methacrylate polymers, composed of charged cationic, hydrophobic and neutral polar groups, with model bacterial membrane. Our simulation data shows that the random ternary polymers can penetrate deep into the membrane interior and partitioning of even a single polymer has a pronounced effect on the membrane structure. Lipid reorganization, on polymer binding, shows a strong affinity of the ternary polymer for anionic POPG lipids and the same is compared with the control case of binary polymers (only cationic and hydrophobic groups). While binary polymers exhibit strong propensity of acquired amphiphilic conformations upon membrane insertion, our results strongly suggest that such amphiphilic conformations are absent in the case of random ternary polymers. The ternary polymers adopt a more folded conformation, staying aligned in the direction of the membrane normal and subsequently penetrating deeper into the membrane interior suggesting a novel membrane partitioning mechanism without amphiphilic conformations. Finally, we also examine the interactions of ternary polymer aggregates with model bacterial membranes, which show that replacing some of the hydrophobic groups by polar groups leads to weakly held ternary aggregates enabling them to undergo rapid partitioning and insertion into membrane interior. Our work thus underscores the role of inclusion of polar groups into the framework of traditional binary biomimetic antimicrobial polymers and suggests different mode of partitioning into bacterial membranes, mimicking antimicrobial mechanism of globular antimicrobial peptides like Defensin.

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Towards designing globular antimicrobial peptide mimics: role of polar functional groups in biomimetic ternary antimicrobial polymers

Soft Matter ◽

10.1039/d0sm01896a ◽

2021 ◽

Author(s):

Garima Rani ◽

Kenichi Kuroda ◽

Satyavani Vemparala

Keyword(s):

Molecular Dynamics ◽

Antimicrobial Peptide ◽

Bacterial Membrane ◽

Simulation Data ◽

Antimicrobial Polymers ◽

Polar Groups ◽

Methacrylate Polymers ◽

Dynamics Simulations ◽

Polar Functional Groups

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The Role of Hydrophobicity in the Stability and pH-Switchability of (RXDX)4 and Coumarin-RXDX Conjugate β-Sheets

10.26434/chemrxiv.11493060 ◽

2020 ◽

Author(s):

Ryan Weber ◽

Martin McCullagh

Keyword(s):

Biological Imaging ◽

Ph Sensing ◽

Hydrophobic Residue ◽

Ideal Candidate ◽

Self Assembling ◽

Sensing Applications ◽

Β Sheets ◽

The Stability ◽

Dynamics Simulations

pH-switchable, self-assembling materials are of interest in biological imaging and sensing applications. Here we propose that combining the pH-switchability of RXDX (X=Ala, Val, Leu, Ile, Phe) peptides and the optical properties of coumarin creates an ideal candidate for these materials. This suggestion is tested with a thorough set of all-atom molecular dynamics simulations. We first investigate the dependence of pH-switchabiliy on the identity of the hydrophobic residue, X, in the bare (RXDX)4 systems. Increasing the hydrophobicity stabilizes the fiber which, in turn, reduces the pH-switchabilty of the system. This behavior is found to be somewhat transferable to systems in which a single hydrophobic residue is replaced with a coumarin containing amino acid. In this case, conjugates with X=Ala are found to be unstable and both pHs while conjugates with X=Val, Leu, Ile and Phe are found to form stable β-sheets at least at neutral pH. The (RFDF)4-coumarin conjugate is found to have the largest relative entropy value of 0.884 +/- 0.001 between neutral and acidic coumarin ordering distributions. Thus, we posit that coumarin-(RFDF)4 containing peptide sequences are ideal candidates for pH-sensing bioelectronic materials.

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Faculty Opinions recommendation of The mechano-sensing role of the unique SH3 insertion in plakin domains revealed by Molecular Dynamics simulations.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.731190888.793568887 ◽

2019 ◽

Author(s):

Kathleen J Green

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Dynamics Simulations

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Exploring secondary interactions and the role of temperature in moisture-contaminated polymer networks through molecular simulations

Soft Matter ◽

10.1039/d0sm02009e ◽

2021 ◽

Vol 17 (10) ◽

pp. 2942-2956

Author(s):

Rishabh D. Guha ◽

Ogheneovo Idolor ◽

Katherine Berkowitz ◽

Melissa Pasquinelli ◽

Landon R. Grace

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Temperature Variation ◽

Polymer Networks ◽

Molecular Simulations ◽

Effect Of Temperature ◽

Secondary Interactions ◽

Dynamics Simulations ◽

Secondary Bonding

We investigated the effect of temperature variation on the secondary bonding interactions between absorbed moisture and epoxies with different morphologies using molecular dynamics simulations.

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A polymeric approach toward resistance-resistant antimicrobial agent with dual-selective mechanisms of action

Science Advances ◽

10.1126/sciadv.abc9917 ◽

2021 ◽

Vol 7 (5) ◽

pp. eabc9917

Author(s):

Silei Bai ◽

Jianxue Wang ◽

Kailing Yang ◽

Cailing Zhou ◽

Yangfan Xu ◽

...

Keyword(s):

Mammalian Cells ◽

Mechanisms Of Action ◽

Model Systems ◽

General Strategy ◽

Antimicrobial Polymers ◽

Bacterial Dna ◽

Bacterial Membranes ◽

Severe Infections ◽

Multiple Drugs ◽

Resistance Rates

Antibiotic resistance is now a major threat to human health, and one approach to combating this threat is to develop resistance-resistant antibiotics. Synthetic antimicrobial polymers are generally resistance resistant, having good activity with low resistance rates but usually with low therapeutic indices. Here, we report our solution to this problem by introducing dual-selective mechanisms of action to a short amidine-rich polymer, which can simultaneously disrupt bacterial membranes and bind to bacterial DNA. The oligoamidine shows unobservable resistance generation but high therapeutic indices against many bacterial types, such as ESKAPE strains and clinical isolates resistant to multiple drugs, including colistin. The oligomer exhibited excellent effectiveness in various model systems, killing extracellular or intracellular bacteria in the presence of mammalian cells, removing all bacteria from Caenorhabditis elegans, and rescuing mice with severe infections. This “dual mechanisms of action” approach may be a general strategy for future development of antimicrobial polymers.

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Prediction of Functional Consequences of Missense Mutations in ANO4 Gene

International Journal of Molecular Sciences ◽

10.3390/ijms22052732 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2732

Author(s):

Nadine Reichhart ◽

Vladimir M. Milenkovic ◽

Christian H. Wetzel ◽

Olaf Strauß

Keyword(s):

Transmembrane Protein ◽

Functional Characterization ◽

Missense Mutations ◽

Mutant Proteins ◽

Functional Consequences ◽

New Perspective ◽

The Stability ◽

Dynamics Simulations ◽

And Function

The anoctamin (TMEM16) family of transmembrane protein consists of ten members in vertebrates, which act as Ca2+-dependent ion channels and/or Ca2+-dependent scramblases. ANO4 which is primarily expressed in the CNS and certain endocrine glands, has been associated with various neuronal disorders. Therefore, we focused our study on prioritizing missense mutations that are assumed to alter the structure and stability of ANO4 protein. We employed a wide array of evolution and structure based in silico prediction methods to identify potentially deleterious missense mutations in the ANO4 gene. Identified pathogenic mutations were then mapped to the modeled human ANO4 structure and the effects of missense mutations were studied on the atomic level using molecular dynamics simulations. Our data show that the G80A and A500T mutations significantly alter the stability of the mutant proteins, thus providing new perspective on the role of missense mutations in ANO4 gene. Results obtained in this study may help to identify disease associated mutations which affect ANO4 protein structure and function and might facilitate future functional characterization of ANO4.

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Molecular insights on poly(N-isopropylacrylamide) coil-to-globule transition induced by pressure

Physical Chemistry Chemical Physics ◽

10.1039/d0cp06452a ◽

2021 ◽

Vol 23 (10) ◽

pp. 5984-5991

Author(s):

Letizia Tavagnacco ◽

Ester Chiessi ◽

Emanuela Zaccarelli

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Polymer Chain ◽

Linear Polymer ◽

Dynamics Simulations ◽

Linear Polymer Chain

By using extensive all-atom molecular dynamics simulations of an atactic linear polymer chain, we unveil the role of pressure in the coil-to-globule transition of poly(N-isopropylacrylamide) (PNIPAM).

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“Newton’s cradle” proton relay with amide–imidic acid tautomerization in inverting cellulase visualized by neutron crystallography

Science Advances ◽

10.1126/sciadv.1500263 ◽

2015 ◽

Vol 1 (7) ◽

pp. e1500263 ◽

Cited By ~ 53

Author(s):

Akihiko Nakamura ◽

Takuya Ishida ◽

Katsuhiro Kusaka ◽

Taro Yamada ◽

Shinya Fushinobu ◽

...

Keyword(s):

Glycoside Hydrolases ◽

Side Chain ◽

Enzymatic Reactions ◽

X Ray Diffraction ◽

Peptide Bonds ◽

Proton Relay ◽

Newton’S Cradle ◽

Dynamics Simulations ◽

Hydrolysis Of

Hydrolysis of carbohydrates is a major bioreaction in nature, catalyzed by glycoside hydrolases (GHs). We used neutron diffraction and high-resolution x-ray diffraction analyses to investigate the hydrogen bond network in inverting cellulase PcCel45A, which is an endoglucanase belonging to subfamily C of GH family 45, isolated from the basidiomycete Phanerochaete chrysosporium. Examination of the enzyme and enzyme-ligand structures indicates a key role of multiple tautomerizations of asparagine residues and peptide bonds, which are finally connected to the other catalytic residue via typical side-chain hydrogen bonds, in forming the “Newton’s cradle”–like proton relay pathway of the catalytic cycle. Amide–imidic acid tautomerization of asparagine has not been taken into account in recent molecular dynamics simulations of not only cellulases but also general enzyme catalysis, and it may be necessary to reconsider our interpretation of many enzymatic reactions.

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