Computational Design of Biologically Active Anticancer Peptides and Their Interactions with Heterogeneous POPC/POPS Lipid Membranes

2019 ◽  
Vol 60 (1) ◽  
pp. 332-341 ◽  
Author(s):  
Maninder Singh ◽  
Vikash Kumar ◽  
Kamakshi Sikka ◽  
Ravi Thakur ◽  
Munesh Kumar Harioudh ◽  
...  
Keyword(s):  
Lipid Membranes ◽  
Computational Design ◽  
Biologically Active ◽  
Anticancer Peptides

scholarly journals Copper-binding anticancer peptides from the piscidin family: an expanded mechanism that encompasses physical and chemical bilayer disruption

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Fatih Comert ◽  
Frank Heinrich ◽  
Ananda Chowdhury ◽  
Mason Schoeneck ◽  
Caitlin Darling ◽  
...  
Keyword(s):  
Lipid Membranes ◽  
Uv Spectroscopy ◽  
Biologically Active ◽  
Copper Binding ◽  
New Paradigm ◽  
Chronic Infections ◽  
Host Defense Peptides ◽  
Anticancer Peptides ◽  
Acyl Chains ◽  
Physical And Chemical

AbstractIn the search for novel broad-spectrum therapeutics to fight chronic infections, inflammation, and cancer, host defense peptides (HDPs) have garnered increasing interest. Characterizing their biologically-active conformations and minimum motifs for function represents a requisite step to developing them into efficacious and safe therapeutics. Here, we demonstrate that metallating HDPs with Cu2+ is an effective chemical strategy to improve their cytotoxicity on cancer cells. Mechanistically, we find that prepared as Cu2+-complexes, the peptides not only physically but also chemically damage lipid membranes. Our testing ground features piscidins 1 and 3 (P1/3), two amphipathic, histidine-rich, membrane-interacting, and cell-penetrating HDPs that are α-helical bound to membranes. To investigate their membrane location, permeabilization effects, and lipid-oxidation capability, we employ neutron reflectometry, impedance spectroscopy, neutron diffraction, and UV spectroscopy. While P1-apo is more potent than P3-apo, metallation boosts their cytotoxicities by up to two- and seven-fold, respectively. Remarkably, P3-Cu2+ is particularly effective at inserting in bilayers, causing water crevices in the hydrocarbon region and placing Cu2+ near the double bonds of the acyl chains, as needed to oxidize them. This study points at a new paradigm where complexing HDPs with Cu2+ to expand their mechanistic reach could be explored to design more potent peptide-based anticancer therapeutics.

scholarly journals Metallated Anticancer Peptides: An Expanded Mechanism that Encompasses Physical and Chemical Bilayer Disruption

2021 ◽  
Author(s):  
Fatih Comert ◽  
Frank Heinrich ◽  
Ananda Chowdhury ◽  
Mason Schoeneck ◽  
Caitlin Darling ◽  
...  
Keyword(s):  
Lipid Membranes ◽  
Uv Spectroscopy ◽  
Biologically Active ◽  
New Paradigm ◽  
Chronic Infections ◽  
Host Defense Peptides ◽  
Anticancer Peptides ◽  
Acyl Chains ◽  
Physical And Chemical ◽  
Chemical Strategy

Abstract In the search for novel broad-spectrum therapeutics to fight chronic infections, inflammation, and cancer, host defense peptides (HDPs) have garnered increasing interest. Characterizing their biologically-active conformations and minimum motifs for function represents a requisite step to developing them into efficacious and safe therapeutics. Here, we demonstrate that metallating HDPs is an effective chemical strategy to improve their cytotoxicity on cancer cells. Mechanistically, we find that the metallated peptides not only physically but also chemically damage lipid membranes. Our testing ground features piscidins 1 and 3 (P1/3), two amphipathic, histidine-rich, membrane-interacting, and cell-penetrating HDPs that are α-helical bound to membranes. To investigate their membrane location, permeabilization effects, and lipid-oxidation capability, we employ neutron reflectometry, impedance spectroscopy, neutron diffraction, and UV spectroscopy. While P1-apo is more potent than P3-apo, metallation boosts their cytotoxicities by up to two-and seven-fold, respectively. Remarkably, P3 is particularly effective at inserting its metallated motif in bilayers, causing water crevices in the hydrocarbon region and placing Cu 2+ near the double bonds of the acyl chains, as needed to oxidize them. This study points at a new paradigm where metallating HDPs to expand their mechanistic reach could be explored to design more potent peptide-based anticancer therapeutics.

scholarly journals Effect of amiloride and some of its analogues of cation transport in isolated frog skin and thin lipid membranes.

1976 ◽  
Vol 68 (1) ◽  
pp. 43-63 ◽  
Author(s):  
D J Benos ◽  
S A Simon ◽  
L J Mandel ◽  
P M Cala
Keyword(s):  
Lipid Membranes ◽  
Frog Skin ◽  
Short Circuit ◽  
Short Circuit Current ◽  
Active Species ◽  
Biologically Active ◽  
Lipid Bilayer Membranes ◽  
Inhibitory Interaction ◽  
Charged Form ◽  
Transport Site

The inhibition of short-circuit current (Isc) in isolated frog skin and the induction of surface potentials in lipid bilayer membranes produced by the diuretic drug amiloride and a number of its chemical analogues was studied. The major conclusions of our study are: (a) The charged form of amiloride is the biologically active species. (b) Both the magnitude of Isc and the amiloride inhibitory effect are sensitive to the ionic milieu bathing the isolated skin, and these two features are modulated at separate and distinct regions on the transport site. (c) Amiloride is very specific in its inhibitory interaction with the Na+ transport site since slight structural modifications can result in significant changes in drug effectiveness. We found that substitutions at pyrazine ring position 5 greatly diminish drug activity, while changes at position 6 are less drastic. Alterations in the guanidinium moiety only diminish activity if the result is a change in the spatial orientation of the amino group carrying the positive charge. (d) Amiloride can bind to and alter the charge on membrane surfaces, but this action cannot explain its highly specific effects in biological systems.

Bimodal Effect of Amphiphilic Biocide Concentrations on Fluidity of Lipid Membranes

1996 ◽  
Vol 51 (11-12) ◽  
pp. 853-858 ◽  
Author(s):  
Marian Podolak ◽  
Dariusz Man ◽  
Stanislaw Waga ◽  
Stanislaw Przestalski
Keyword(s):  
Binding Energy ◽  
Lipid Membranes ◽  
Positive Charge ◽  
Egg Yolk ◽  
Biologically Active ◽  
Double Positive ◽  
Dipole System ◽  
Monovalent Ions ◽  
Single Positive ◽  
High Concentrations

Abstract Using the spin label method (ESR) it has been shown that biologically active, amphiphilic compounds (quaternary ammonium salts -AS) containing polar heads with single and double positive charge caused, at low concentrations, decrease fluidity of liposome membranes formed with egg yolk lecithin (EYL). At higher concentrations an increase in fluidity was observed. With compounds having a single positive charge minimum fluidity of membrane structure occurs in the range of 1 to 3%, with compounds containing double positive charge -in the range of 4 -6 % . That effect does not depend on polar head size and length of alkyl chains of the AS used. Analysis of the electrostatic interaction between positive charges and dipole system suggest that at low ion concentrations the binding energy of the system increases, while it decreases at high concentrations. For the model presented, maxi­mum of binding energy of the system occurs at 3% of positive monovalent ions and at 6% of positive divalent ions admixed.

scholarly journals Computational Design of a Biologically Active Enzyme

Science ◽  
2004 ◽  
Vol 304 (5679) ◽  
pp. 1967-1971 ◽  
Author(s):  
M. A. Dwyer
Keyword(s):  
Computational Design ◽  
Active Enzyme ◽  
Biologically Active

scholarly journals The First Structure of a Lantibiotic Immunity Protein, SpaI from Bacillus subtilis, Reveals a Novel Fold

2012 ◽  
Vol 287 (42) ◽  
pp. 35286-35298 ◽  
Author(s):  
Nina A. Christ ◽  
Sophie Bochmann ◽  
Daniel Gottstein ◽  
Elke Duchardt-Ferner ◽  
Ute A. Hellmich ◽  
...  
Keyword(s):  
Bacillus Subtilis ◽  
Lipid Membranes ◽  
Biologically Active ◽  
Gram Positive ◽  
Gram Positive Bacteria ◽  
Lipid Ii ◽  
Terminal Fragment ◽  
Terminal Amino ◽  
Immunity Mechanism ◽  
Producer Strains

Lantibiotics are peptide-derived antibiotics that inhibit the growth of Gram-positive bacteria via interactions with lipid II and lipid II-dependent pore formation in the bacterial membrane. Due to their general mode of action the Gram-positive producer strains need to express immunity proteins (LanI proteins) for protection against their own lantibiotics. Little is known about the immunity mechanism protecting the producer strain against its own lantibiotic on the molecular level. So far, no structures have been reported for any LanI protein. We solved the structure of SpaI, a LanI protein from the subtilin producing strain Bacillus subtilis ATCC 6633. SpaI is a 16.8-kDa lipoprotein that is attached to the outside of the cytoplasmic membrane via a covalent diacylglycerol anchor. SpaI together with the ABC transporter SpaFEG protects the B. subtilis membrane from subtilin insertion. The solution-NMR structure of a 15-kDa biologically active C-terminal fragment reveals a novel fold. We also demonstrate that the first 20 N-terminal amino acids not present in this C-terminal fragment are unstructured in solution and are required for interactions with lipid membranes. Additionally, growth tests reveal that these 20 N-terminal residues are important for the immunity mediated by SpaI but most likely are not part of a possible subtilin binding site. Our findings are the first step on the way of understanding the immunity mechanism of B. subtilis in particular and of other lantibiotic producing strains in general.

scholarly journals De novo design of transmembrane β-barrels

2020 ◽  
Author(s):  
Anastassia A. Vorobieva ◽  
Paul White ◽  
Binyong Liang ◽  
Jim E Horne ◽  
Asim K. Bera ◽  
...  
Keyword(s):  
Lipid Bilayers ◽  
Single Molecule ◽  
First Principles ◽  
Lipid Membranes ◽  
De Novo ◽  
Computational Design ◽  
Protein Sequencing ◽  
Naturally Occurring ◽  
Transmembrane Pores ◽  
Almost All

AbstractThe ability of naturally occurring transmembrane β-barrel proteins (TMBs) to spontaneously insert into lipid bilayers and form stable transmembrane pores is a remarkable feat of protein evolution and has been exploited in biotechnology for applications ranging from single molecule DNA and protein sequencing to biomimetic filtration membranes. Because it has not been possible to design TMBs from first principles, these efforts have relied on re-engineering of naturally occurring TMBs that generally have a biological function very different from that desired. Here we leverage the power of de novo computational design coupled with a “hypothesis, design and test” approach to determine principles underlying TMB structure and folding, and find that, unlike almost all other classes of protein, locally destabilizing sequences in both the β-turns and β-strands facilitate TMB expression and global folding by modulating the kinetics of folding and the competition between soluble misfolding and proper folding into the lipid bilayer. We use these principles to design new eight stranded TMBs with sequences unrelated to any known TMB and show that they insert and fold into detergent micelles and synthetic lipid membranes. The designed proteins fold more rapidly and reversibly in lipid membranes than the TMB domain of the model native protein OmpA, and high resolution NMR and X-ray crystal structures of one of the designs are very close to the computational model. The ability to design TMBs from first principles opens the door to custom design of TMBs for biotechnology and demonstrates the value of de novo design to investigate basic protein folding problems that are otherwise hidden by evolutionary history.One sentence summarySuccess in de novo design of transmembrane β-barrels reveals geometric and sequence constraints on the fold and paves the way to design of custom pores for sequencing and other single-molecule analytical applications.

scholarly journals Design of Biologically Active Binary Protein 2D Materials

2020 ◽  
Author(s):  
Ariel J. Ben-Sasson ◽  
Joseph Watson ◽  
William Sheffler ◽  
Matthew Camp Johnson ◽  
Alice Bittleston ◽  
...  
Keyword(s):  
Cell Surface ◽  
Cell Biology ◽  
Computational Design ◽  
Building Blocks ◽  
Computational Method ◽  
Biologically Active ◽  
Cell Surface Receptor ◽  
Two Dimensional ◽  
Synthetic Cell

AbstractProteins that assemble into ordered two-dimensional arrays such as S-layers1,2 and designed analogues3–5 have intrigued bioengineers,6,7 but with the exception of a single lattice formed through non-rigid template streptavidin linkers,8 they are constituted from just one protein component. For modulating assembly dynamics and incorporating more complex functionality, materials composed of two components would have considerable advantages.9–12 Here we describe a computational method to generate de-novo binary 2D non-covalent co-assemblies by designing rigid asymmetric interfaces between two distinct protein dihedral building-blocks. The designed array components are soluble at mM concentrations, but when combined at nM concentrations, rapidly assemble into nearly-crystalline micrometer-scale p6m arrays nearly identical to the computational design model in vitro and in cells without the need of a two-dimensional support. Because the material is designed from the ground up, the components can be readily functionalized, and their symmetry reconfigured, enabling formation of ligand arrays with distinguishable surfaces to drive extensive receptor clustering, downstream protein recruitment, and signaling. Using quantitative microscopy we show that arrays assembled on living cells have component stoichiometry and likely structure similar to arrays formed in vitro, suggesting that our material can impose order onto fundamentally disordered substrates like cell membranes. We find further that in sharp contrast to previously characterized cell surface receptor binding assemblies such as antibodies and nanocages, which are rapidly endocytosed, large arrays assembled at the cell surface suppress endocytosis in a tunable manner, with potential therapeutic relevance for extending receptor engagement and immune evasion. Our work paves the way towards synthetic cell biology, where a new generation of multi-protein macroscale materials is designed to modulate cell responses and reshape synthetic and living systems.One Sentence SummaryCo-assembling binary 2D protein crystals enables robust formation of complex large scale ordered biologically active materials

Nitro derivatives of quinoline and quinoline N-oxide as low-cost alternative for the treatment of SARS-CoV-2 infection

2020 ◽  
Author(s):  
Letícia Cristina Assis ◽  
Alexandre Alves de Castro ◽  
João Paulo Almirão de Jesus ◽  
Eugenie Nepovimova ◽  
Kamil Kuca ◽  
...  
Keyword(s):  
Transmission Rate ◽  
Low Cost ◽  
Computational Design ◽  
Docking Studies ◽  
Biologically Active ◽  
New Drugs ◽  
Time Space ◽  
Short Period ◽  
Nitro Derivatives ◽  
Derivatives Of

Abstract A new and more aggressive strain of coronavirus, known as SARS-CoV-2, which is highly contagious, has rapidly spread across the planet within a short period of time. Due to its high transmission rate and the significant time–space between infection and manifestation of symptoms, the WHO recently declared this a pandemic. Because of the exponentially growing number of new cases of both infections and deaths, development of new therapeutic options to help fight this pandemic is urgently needed. The target molecules of this study were the nitro derivatives of quinoline and quinoline N-oxide. Computational design at the DFT level, docking studies, and molecular dynamics methods as a well-reasoned strategy will aid in elucidating the fundamental physicochemical properties and molecular functions of a diversity of compounds, directly accelerating the process of discovering new drugs. In this study, we discovered isomers based on the nitro derivatives of quinoline and quinoline N-oxide, which are biologically active compounds and may be low-cost alternatives for the treatment of infections induced by SARS-CoV-2.

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