scholarly journals Solvent Remodeling in Single-Chain Amphiphilic Heteropolymer Systems

2021 ◽  
Author(s):  
Shayna Hilburg ◽  
Alfredo Alexander-Katz
Keyword(s):  
Organic Solvent ◽  
Electrostatic Interactions ◽  
Environmental Changes ◽  
Hydrophobic Effect ◽  
Single Chain ◽  
Activation Barriers ◽  
Low Dielectric ◽  
Molecular Behavior ◽  
High Temperature Anneal ◽  
Dynamics Simulations

Through molecular dynamics simulations, we demonstrate how single-chain nanoparticles (SCNPs) assembled via transient linkages in water can remodel in organic solvent. Methacrylate-based random heteropolymers (RHPs) have shown promise in an assortment of applications that harness their bio-inspired properties. While their molecular behavior has been broadly characterized in water, many newer applications include the use of organic solvent rather than bio-mimetic conditions in which the polymer assemblies, typically driven by the hydrophobic effect, are less well understood. Here, we examine a specific RHP system which forms compact globular morphologies in highly polar and non-polar environments while adopting extended conformations in solvents of intermediate polarity. We also demonstrate the pivotal role of electrostatic interactions between charge groups in low dielectric mediums. Finally, we compare high temperature anneal cycles to room temperature equilibrations to illuminate activation barriers to remodeling upon environmental changes.

scholarly journals Strong reduction of the chain rigidity of hyaluronan by selective binding of Ca2+ ions

2020 ◽  
Author(s):  
G. Giubertoni ◽  
A. Pérez de Alba Ortíz ◽  
F. Bano ◽  
X. Zhang ◽  
R.J. Linhardt ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Electrostatic Interactions ◽  
Structural Changes ◽  
Polymer Chains ◽  
Single Chain ◽  
Molecular Hydrogen Bond ◽  
Dynamics Simulations ◽  
Chain Force ◽  
Molecular Picture

ABSTRACTThe biological functions of natural polyelectrolytes are strongly influenced by the presence of ions, which bind to the polymer chains and thereby modify their properties. Although the biological impact of such modifications is well-recognized, a detailed molecular picture of the binding process and of the mechanisms that drive the subsequent structural changes in the polymer is lacking. Here, we study the molecular mechanism of the condensation of calcium, a divalent cation, on hyaluronan, a ubiquitous polymer in human tissues. By combining two-dimensional infrared spectroscopy experiments with molecular dynamics simulations, we find that calcium specifically binds to hyaluronan at millimolar concentrations. Because of its large size and charge, the calcium cation can bind simultaneously to the negatively charged carboxylate group and the amide group of adjacent saccharide units. Molecular dynamics simulations and single-chain force spectroscopy measurements provide evidence that the binding of the calcium ions weakens the intra-molecular hydrogen-bond network of hyaluronan, increasing the flexibility of the polymer chain. We also observe that the binding of calcium to hyaluronan saturates at a maximum binding fraction of ~10-15 mol %. This saturation indicates that the binding of Ca2+ strongly reduces the probability of subsequent binding of Ca2+ at neighboring binding sites, possibly as a result of enhanced conformational fluctuations and/or electrostatic repulsion effects. Our findings provide a detailed molecular picture of ion condensation, and reveal the severe effect of a few, selective and localized electrostatic interactions on the rigidity of a polyelectrolyte chain.TOC

Solubilization of Itraconazole by Surfactants and Phospholipid-Surfactant Mixtures: Interplay of Amphiphile Structure, pH and Electrostatic Interactions

2020 ◽  
Author(s):  
Zahari Vinarov ◽  
Gabriela Gancheva ◽  
Nikola Burdzhiev ◽  
Slavka S. Tcholakova
Keyword(s):  
Nmr Spectroscopy ◽  
Electrostatic Interactions ◽  
Triazole Ring ◽  
Water Soluble ◽  
Single Chain ◽  
Surfactant Mixtures ◽  
Solubilization Capacity ◽  
Water Soluble Drugs ◽  
Hydrophobic Chain ◽  
Brick Dust

Although surfactants are frequently used in enabling formulations of poorly water-soluble drugs, the link between their structure and drug solubilization capacity is still unclear. We studied the solubilization of the “brick-dust” molecule itraconazole by 16 surfactants and 3 phospholipid:surfactant mixtures. NMR spectroscopy was used to study in more details the drug-surfactant interactions. Very high solubility of itraconazole (up to 3.6 g/L) was measured in anionic surfactant micelles at pH = 3, due to electrostatic attraction between the oppositely charged (at this pH) drug and surfactant molecules. <sup>1</sup>H NMR spectroscopy showed that itraconazole is ionized at two sites (2+ charge) at these conditions: in the phenoxy-linked piperazine nitrogen and in the dioxolane-linked triazole ring. The increase of amphiphile hydrophobic chain length had a markedly different effect, depending on the amphiphile type: the solubilization capacity of single-chain surfactants increased, whereas a decrease was observed for double-chained surfactants (phosphatidylglycerols). The excellent correlation between the chain melting temperatures of phosphatidylglycerols and itraconazole solubilization illustrated the importance of hydrophobic chain mobility. This study provides rules for selection of itraconazole solubilizers among classical single-chain surfactants and phospholipids. The basic physics underpinning the described effects suggests that these rules should be transferrable to other “brick-dust” molecules.

Sequence Specificity Despite Intrinsic Disorder: How a Disease-Associated Val/Met Polymorphism Shifts Tertiary Interactions in a Long Disordered Protein

2019 ◽  
Author(s):  
Ruchi Lohia ◽  
Reza Salari ◽  
Grace Brannigan
Keyword(s):  
Secondary Structure ◽  
Electrostatic Interactions ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Sequence Specificity ◽  
Intrinsically Disordered ◽  
Specific Effects ◽  
Heterogeneous Polymer ◽  
Non Local ◽  
Dynamics Simulations

<div>The role of electrostatic interactions and mutations that change charge states in intrinsically disordered proteins (IDPs) is well-established, but many disease-associated mutations in IDPs are charge-neutral. The Val66Met single nucleotide polymorphism (SNP) encodes a hydrophobic-to-hydrophobic mutation at the midpoint of the prodomain of precursor brain-derived neurotrophic factor (BDNF), one of the earliest SNPs to be associated with neuropsychiatric disorders, for which the underlying molecular mechanism is unknown. Here we report on over 250 μs of fully-atomistic, explicit solvent, temperature replica exchange molecular dynamics simulations of the 91 residue BDNF prodomain, for both the V66 and M66 sequence.</div><div>The simulations were able to correctly reproduce the location of both local and non-local secondary changes due to the Val66Met mutation when compared with NMR spectroscopy. We find that the local structure change is mediated via entropic and sequence specific effects. We show that the highly disordered prodomain can be meaningfully divided into domains based on sequence alone. Monte Carlo simulations of a self-excluding heterogeneous polymer, with monomers representing each domain, suggest the sequence would be effectively segmented by the long, highly disordered polyampholyte near the sequence midpoint. This is qualitatively consistent with observed interdomain contacts within the BDNF prodomain, although contacts between the two segments are enriched relative to the self-excluding polymer. The Val66Met mutation increases interactions across the boundary between the two segments, due in part to a specific Met-Met interaction with a Methionine in the other segment. This effect propagates to cause the non-local change in secondary structure around the second methionine, previously observed in NMR. The effect is not mediated simply via changes in inter-domain contacts but is also dependent on secondary structure formation around residue 66, indicating a mechanism for secondary structure coupling in disordered proteins. </div>

scholarly journals Characterization of design grammar of peptides for regulating liquid droplets and aggregates of FUS

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kiyoto Kamagata ◽  
Rika Chiba ◽  
Ichiro Kawahata ◽  
Nanako Iwaki ◽  
Saori Kanbayashi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Electrostatic Interactions ◽  
Amyloid Fibrils ◽  
Droplet Formation ◽  
Liquid Droplets ◽  
Proof Of Concept ◽  
Aggregate Formation ◽  
Fused In Sarcoma ◽  
Dynamics Simulations

AbstractLiquid droplets of aggregation-prone proteins, which become hydrogels or form amyloid fibrils, are a potential target for drug discovery. In this study, we proposed an experiment-guided protocol for characterizing the design grammar of peptides that can regulate droplet formation and aggregation. The protocol essentially involves investigation of 19 amino acid additives and polymerization of the identified amino acids. As a proof of concept, we applied this protocol to fused in sarcoma (FUS). First, we evaluated 19 amino acid additives for an FUS solution and identified Arg and Tyr as suppressors of droplet formation. Molecular dynamics simulations suggested that the Arg additive interacts with specific residues of FUS, thereby inhibiting the cation–π and electrostatic interactions between the FUS molecules. Second, we observed that Arg polymers promote FUS droplet formation, unlike Arg monomers, by bridging the FUS molecules. Third, we found that the Arg additive suppressed solid aggregate formation of FUS, while Arg polymer enhanced it. Finally, we observed that amyloid-forming peptides induced the conversion of FUS droplets to solid aggregates of FUS. The developed protocol could be used for the primary design of peptides controlling liquid droplets and aggregates of proteins.

scholarly journals Spatial segregation of mixed-sized counterions in dendritic polyelectrolytes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
J. S. Kłos ◽  
J. Paturej
Keyword(s):  
Electrostatic Interactions ◽  
Spatial Separation ◽  
Excluded Volume ◽  
The Core ◽  
Bjerrum Length ◽  
Two Component ◽  
Conformational Properties ◽  
Dynamics Simulations ◽  
Two Parameters ◽  
Swelling Factor

AbstractLangevin dynamics simulations are utilized to study the structure of a dendritic polyelectrolyte embedded in two component mixtures comprised of conventional (small) and bulky counterions. We vary two parameters that trigger conformational properties of the dendrimer: the reduced Bjerrum length, $$\lambda _B^*$$ λ B ∗ , which controls the strength of electrostatic interactions and the number fraction of the bulky counterions, $$f_b$$ f b , which impacts on their steric repulsion. We find that the interplay between the electrostatic and the counterion excluded volume interactions affects the swelling behavior of the molecule. As compared to its neutral counterpart, for weak electrostatic couplings the charged dendrimer exists in swollen conformations whose size remains unaffected by $$f_b$$ f b . For intermediate couplings, the absorption of counterions into the pervaded volume of the dendrimer starts to influence its conformation. Here, the swelling factor exhibits a maximum which can be shifted by increasing $$f_b$$ f b . For strong electrostatic couplings the dendrimer deswells correspondingly to $$f_b$$ f b . In this regime a spatial separation of the counterions into core–shell microstructures is observed. The core of the dendrimer cage is preferentially occupied by the conventional ions, whereas its periphery contains the bulky counterions.

scholarly journals Chromatin remodelers couple inchworm motion with twist-defect formation to slide nucleosomal DNA

2018 ◽  
Author(s):  
Giovanni B. Brandani ◽  
Shoji Takada
Keyword(s):  
Genome Organization ◽  
Electrostatic Interactions ◽  
Defect Formation ◽  
Energy Landscape ◽  
Molecular Machines ◽  
Biological Processes ◽  
Complete Understanding ◽  
Chromatin Remodelers ◽  
Nucleosomal Dna ◽  
Dynamics Simulations

ABSTRACTATP-dependent chromatin remodelers are molecular machines that control genome organization by repositioning, ejecting, or editing nucleosomes, activities that confer them essential regulatory roles on gene expression and DNA replication. Here, we investigate the molecular mechanism of active nucleosome sliding by means of molecular dynamics simulations of the Snf2 remodeler in complex with a nucleosome. During its inchworm motion driven by ATP consumption, the remodeler overwrites the original nucleosome energy landscape via steric and electrostatic interactions to induce sliding of nucleosomal DNA unidirectionally. The sliding is initiated at the remodeler binding location via the generation of twist defects, which then spontaneously propagate to complete sliding throughout the entire nucleosome. We also reveal how remodeler mutations and DNA sequence control active nucleosome repositioning, explaining several past experimental observations. These results offer a detailed mechanistic picture of remodeling important for the complete understanding of these important biological processes.

scholarly journals SLC6A14, a Pivotal Actor on Cancer Stage: When Function Meets Structure

2019 ◽  
Vol 24 (9) ◽  
pp. 928-938 ◽  
Author(s):  
Luca Palazzolo ◽  
Chiara Paravicini ◽  
Tommaso Laurenzi ◽  
Sara Adobati ◽  
Simona Saporiti ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Amino Acid ◽  
Molecular Dynamics Simulations ◽  
Electrostatic Interactions ◽  
Amino Acid Residues ◽  
Dibasic Amino Acid ◽  
Novel Target ◽  
Function Relationship ◽  
Dynamics Simulations

SLC6A14 (ATB0,+) is a sodium- and chloride-dependent neutral and dibasic amino acid transporter that regulates the distribution of amino acids across cell membranes. The transporter is overexpressed in many human cancers characterized by an increased demand for amino acids; as such, it was recently acknowledged as a novel target for cancer therapy. The knowledge on the molecular mechanism of SLC6A14 transport is still limited, but some elegant studies on related transporters report the involvement of the 12 transmembrane α-helices in the transport mechanism, and describe structural rearrangements mediated by electrostatic interactions with some pivotal gating residues. In the present work, we constructed a SLC6A14 model in outward-facing conformation via homology modeling and used molecular dynamics simulations to predict amino acid residues critical for substrate recognition and translocation. We docked the proteinogenic amino acids and other known substrates in the SLC6A14 binding site to study both gating regions and the exposed residues involved in transport. Interestingly, some of these residues correspond to those previously identified in other LeuT-fold transporters; however, we could also identify a novel relevant residue with such function. For the first time, by combined approaches of molecular docking and molecular dynamics simulations, we highlight the potential role of these residues in neutral amino acid transport. This novel information unravels new aspects of the human SLC6A14 structure–function relationship and may have important outcomes for cancer treatment through the design of novel inhibitors of SLC6A14-mediated transport.

scholarly journals Human DNA Telomeres in Presence of Oxidative Lesions: The Crucial Role of Electrostatic Interactions on the Stability of Guanine Quadruplexes

Antioxidants ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 337 ◽  
Author(s):  
Hognon ◽  
Gebus ◽  
Barone ◽  
Monari
Keyword(s):  
Electrostatic Interactions ◽  
Empty Site ◽  
Quadruplex Structure ◽  
Abasic Sites ◽  
Human Dna ◽  
Guanine Quadruplex ◽  
Guanine Base ◽  
The Stability ◽  
Dynamics Simulations

By using all atom molecular dynamics simulations, we studied the behavior of human DNA telomere sequences in guanine quadruplex (G4) conformation and in the presence of oxidative lesions, namely abasic sites. In particular, we evidenced that while removing one guanine base induces a significant alteration and destabilization of the involved leaflet, human telomere oligomers tend, in most cases, to maintain at least a partial quadruplex structure, eventually by replacing the empty site with undamaged guanines of different leaflets. This study shows that (i) the disruption of the quadruplex leaflets induces the release of at least one of the potassium cations embedded in the quadruplex channel and that (ii) the electrostatic interactions of the DNA sequence with the aforementioned cations are fundamental to the maintenance of the global quadruplex structure.

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