Molecular Description Research Articles

The molecular dynamics description of electric field effect on nano-pumping performance of boron-nitride nanotube (BNNT) in the presence of vacancy defect

The electric field is an electric exclusivity related to each point in space when the charge is shown in any form. This parameter affects the various physical process in actual applications. The external electric field (EEF) effect on nano-pumping (NP) proficiency of defected boron nitride nanotube (BNNT) using the Molecular Dynamics (MD) method and LAMMPs package is described in this study. Our simulations are done in two main steps: equilibrium and the NP processes. Equilibrium outputs show the physical stability of modeled BNNT/C20/Cu system as a nano-pumper arrangement after t = 10 ns. The kinetic energy (KE) of the atomic compound converges to 85.64 eV in the final step of the equilibrium phase. In a defined system, C20 molecule displacement shows the NP procedure. The NP process in defected BNNT is detected after 13.51 ps. The EEF implementation inside the MD box causes the NP performance of the pristine structure to improve, and NP time converged to 10.03 ps. Furthermore, the amplitude of EEF is an essential parameter in NP simulations. MD outputs are predicted by setting this parameter at 0.7 V/m and the behavior of defected BNNT structure as a nano-pumper is optimized. We expected that our reported results in this computational work cause optimization of related applications such as the drug delivery process in actual cases.

Clinical and molecular features of four Brazilian families with multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome characterized by its clinical variability and complexity in diagnosis and treatment. We performed both clinical and molecular descriptions of four families with MEN1 in a follow-up at a tertiary center in Brasília. From a preliminary review of approximately 500 medical records of patients with pituitary neuroendocrine tumor (PitNET) from the database of the Neuroendocrinology Outpatient Clinic of the University Hospital of Brasília, a total of 135 patients met the criteria of at least two affected family members. From this cohort, we have identified 34 families: only four with a phenotype of MEN1 and the other 30 families with the phenotype of familial isolated pituitary adenoma (FIPA). Eleven patients with a clinical diagnosis of MEN1 from these four families were selected. Variants in MEN1 gene were identified in all families. One individual from each family underwent genetic testing using targeted high-throughput sequencing (HTS). All patients had primary hyperparathyroidism (PHPT), and the second most common manifestation was PitNET. One individual had well-differentiated liposarcoma, which has been previously reported in a single case of MEN1. Three variants previously described in the database and a novel variant in exon 2 have been found. The study allowed the genotypic and phenotypic characterization of families with MEN1 in a follow-up at a tertiary center in Brasília.

Application of dissipative particle dynamics to interfacial systems: Parameterization and scaling

Dissipative Particle Dynamics (DPD) is a stochastic particle model that is able to simulate larger systems over longer time scales than atomistic modeling approaches by including the concept of coarse-graining. Whether standard DPD can cover the whole mesoscale by changing the level of coarse-graining is still an open issue. A scaling scheme originally developed by Füchslin et al. (2009) was here applied to interfacial systems as one of the most successful uses of the classical DPD method. In particular, equilibrium properties such as the interfacial tension were analyzed at different levels of coarse-graining for planar oil–water interfaces with and without surfactant. A scaling factor for the interfacial tension was found due to the combined effect of the scaling scheme and the coarse-graining parameterization. Although the level of molecular description was largely decreased, promising results showed that it is possible to conserve the interfacial tension trend at increasing surfactant concentrations, remarkably reducing modeling complexity. The same approach was also employed to simulate a droplet configuration. Both planar and droplet conformations were maintained, showing that typical domain formations of multi-component systems can be performed in DPD by means of the scaling procedure. Therefore, we explored the possibility of describing oil–water and oil–water–surfactant systems in standard DPD using a scaling scheme with the aim of highlighting its advantages and limitations.

Gut Bacterial Microbiota of The Honeybee, Apis mellifera (Hymenoptera: Apidae) with a New Host Record

Gut microbial communities of the honeybee, Apis mellifera L. have vital functions in food digestion, providing essential nutrients, improving immune system against pathogens, and detoxifying harmful molecules. The objective of this study was to characterize the core gut bacterial community of newly emerged A. mellifera queens and workers from southeastern Turkey. A total of newly emerged 15 queens and 30 workers were collected from the same apiary. The alimentary tract of collected samples was dissected under sterile conditions. Culture based isolation was performed from the digestive tract of the collected samples to obtain a pure microbe culture. The chemical, morphological and molecular description of each bacteria were accurately done via employment of pure culture. Five bacterial isolates were successfully isolated from the A. mellifera alimentary tract and purified. Molecular and biochemical identification showed that the isolates were Bacillus pumilus, Bacillus subtilis, Bacillus cereus (Firmicutes: Bacillaceae) (MZ540443, MZ540444, MZ540445), Staphylococcus haemolyticus (Firmicutes: Staphylococcaceae) (MZ540447), and Paenibacillus glucanolyticus (Firmicutes: Paenibacillaceae) (MZ540446). This study is the first to report the presence of P. glucanolyticus in gut bacterial community of A. mellifera.

QSPR modeling for the prediction of the triplet yield of singlet fission materials

Singlet excitons fission (SF) into triplet excitons can enhance the efficiency of solar cells while reducing the heat loss in light absorption systems, but requires photostable materials with high triplet yield. We use Support Vector Regression (SVR) to establish a Quantitative Structure-Property Relationship (QSPR) model for perdition the triplet yield (ΦSF) of singlet fission materials (tetracene, pentacene, and perylenedimide derivatives, etc.). Minimum redundancy maximum relevance (mRMR), Floating front search (FFS) and Grid-search were used to select property molecular descriptions and parameter optimization, then the SVR model was established to predict the ΦSF of these compounds. The correlation coefficient R values of leave one out cross-validation (LOOCV) test and external validation test set were 0.88 and 0.93, respectively. The results show that the SVR-QSPR model has strong generalization ability, can predict the ΦSF value of singlet fission materials effectively and guide significance for developing highly efficient solar cells.

Insights into autoregulation of a membrane protein complex by its cytoplasmic domains.

Membrane transporters mediate the passage of molecules across membranes and are essential for cellular function. While the transmembrane region of these proteins is responsible for substrate transport, often the cytoplasmic regions are required for modulating their activity. However, it can be difficult to obtain atomic-resolution descriptions of these autoregulatory domains by classical structural biology techniques, especially if they lack a single, defined structure. The betaine permease, BetP, a homotrimer, is a well-studied example of a membrane protein whose autoregulation depends on cytoplasmic N- and C-terminal segments. These domains sense and transduce changes in K+ concentration and in lipid bilayer properties caused by osmotic stress. However, structural data for these terminal domains is incomplete, hindering a clear description of the molecular mechanism of autoregulation. Here we used µs-scale molecular simulations of the BetP trimer to compare reported conformations of the 45 amino-acid long C-terminal tails. The simulations indicate that the conformation derived from EM data represents a more stable global orientation of the C-terminal segment under downregulating conditions, while also providing a detailed molecular description of its dynamics and interactions with lipids and neighboring transporter subunits. A missing piece of the puzzle is how the N-terminal segment is involved, since its dynamic nature has prevented structural characterization. Using Rosetta to generate ensembles of de novo conformations obtained in the context of the EM-derived structure clearly predicts secondary structure elements within the N-terminal tail, and that its potential interactions are limited to the protomer in the counterclockwise direction (viewed from the cytoplasm). Since each C-terminal tail only contacts the protomer in the clockwise direction, these results indicate an intricate interplay between the three protomers of BetP in the downregulated protein and a multi-directionality that may facilitate autoregulation of betaine transport.

Understanding the assembly mechanism of the twin arginine transport system.

The twin-arginine protein translocation (Tat) system transports folded proteins across the bacterial cytoplasmic membrane and the thylakoid membrane of chloroplasts. The Escherichia coli Tat system comprises TatC and two additional sequence-related proteins, TatA and TatB. Tat-directed proteins are distinguished by a conserved twin-arginine (RR-) motif in their signal sequences. Substrate binding promotes a conformation rearrangement of the Tat complex. TatA is then recruited to the substrate activated TatBC complex, where it polymerizes to form the substrate translocation pathway. The central challenge in understanding Tat transport is to determine how the Tat components are assembled to form the active translocon allowing folded substrates to be transferred across the membrane bilayer. In this work, we used molecular dynamics simulations to describe the TatA oligomerization mechanism and how the translocation pathway is formed. Our results show that the Tat complex becomes more dynamic after substrate binding. The presence of the substrate induces a “breathing” movement, increasing the separation between two adjacent TatC subunits. Moreover, our results also suggest that substrate binding induces an asymmetry in the Tat Complex, favouring TatA aggregation around the interface opposite to the TatC subunit where the signal peptide is bound. The TatA oligomer is anchored to the Tat complex through contacts with the TM1 and the TM6 of the adjacent TatC subunits, which promotes a local weakening of the membrane bilayer. Our extensive coarse-grained MD simulations provide a molecular description of the Tat translocon assembly and new insights into the Tat transport cycle.

Exogenous Protein Delivery of Ionic Liquid-Mediated HMGB1 Coating on Titanium Implants.

Strategies for modifying titanium (Ti) implant surfaces are becoming increasingly popular to enhance osseointegration during acute and inflammatory healing stages. In this study, two dicationic imidazolium-based ionic liquids (IonLs) containing phenylalanine and methionine anions (IonL-Phe(1,10-bis(3-methylimidazolium-1-yl)decane diphenylalanine) and IonL-Met(1,10-bis(3-methylimidazolium-1-yl)decane dimethionine)) were investigated to stably deliver exogenous proteins on Ti to promote osseointegration. The protein selected for this study is High-Mobility Group Box 1 (HMGB1), which recruits inflammatory and mesenchymal stem cells to the implantation site, contributing to healing. To explore IonL-Ti interactions and HMGB1 stability on the IonL-coated surface, experimental characterization techniques including X-ray photoelectron spectroscopy, scanning electron microscopy, dynamic scanning calorimetry (DSC), and liquid chromatography mass spectrometry (LC-MS) were used along with molecular dynamics (MD) computer simulations to provide a detailed molecular level description. Results show well-structured IonL molecules on the Ti surface that impact protein crystallization and coating morphology. IonL cations and anions were found to bind strongly to oppositely charged residues of the protein. LC-MS/MS reveals that HMGB1 B-box lysine residues bind strongly to the IonLs. Stronger interactions of HMGB1 with Ion-Phe in contrast to IonL-Met results in greater retention capacity of HMGB1 in the IonL-Phe coating. Overall, this study provides evidence that the selected IonLs strongly interact with HMGB1, which can be a potential surface treatment for bone-implantable Ti devices.

Disordered Domain Shifts the Conformational Ensemble of the Folded Regulatory Domain of the Multidomain Oncoprotein c-Src.

c-Src kinase is a multidomain non-receptor tyrosine kinase that aberrantly phosphorylates several signaling proteins in cancers. Although the structural properties of the regulatory domains (SH3-SH2) and the catalytic kinase domain have been extensively characterized, there is less knowledge about the N-terminal disordered region (SH4UD) and its interactions with the other c-Src domains. Here, we used domain-selective isotopic labeling combined with the small-angle neutron scattering contrast matching technique to study SH4UD interactions with SH3-SH2. Our results show that in the presence of SH4UD, the radius of gyration (Rg) of SH3-SH2 increases, indicating that it has a more extended conformation. Hamiltonian replica exchange molecular dynamics simulations provide a detailed molecular description of the structural changes in SH4UD-SH3-SH2 and show that the regulatory loops of SH3 undergo significant conformational changes in the presence of SH4UD, while SH2 remains largely unchanged. Overall, this study highlights how a disordered region can drive a folded region of a multidomain protein to become flexible, which may be important for allosteric interactions with binding partners. This may help in the design of therapeutic interventions that target the regulatory domains of this important family of kinases.

Molecular Characterization of Mesocestoides litteratus (Cestoda: Cyclophyllidea: Mesocestoididae) Tetrathyridium Isolated from Two Species of Rodents from Iran.

Mesocestoides spp. are Cyclophyllidean tapeworms with zoonotic importance. The current study aimed to investigate the molecular characteristics of Mesocestoides larvae (tetrathyridium) isolated from the abdominal cavity of persion jird, Meriones persicus, and from the liver of grey hamster, Cricetulus migratorius, in Ardabil Province, northwest Iran. Genomic DNA of the isolates of Mesocestoides tetrathyridium were extracted, and mitochondrial gene of cytochrome-c oxidase subunit1 (cox1) was amplified. Sequencing of PCR products were performed and phylogenic analysis was run using MEGA 6.0 software. Both isolates were identified as Mesocestoides litteratus, showing high identity with M. litteratus sequences available in GenBank. Also, they had 100% homology to each other. Intra-species variation within isolates of M. litteratus were 0-2.4%. The phylogenetic reconstruction based on the partial sequence of the cox1 gene showed that our sequences of M. litteratus were clustered with M. litteratus isolates from Slovakia, Netherlands, Germany and Italy. This is the first molecular description of M. litteratus from M. persicus and C. migratorius. Phylogenetic analysis illustrated that M. litteratus isolates of the current study had very high identities with the isolates of this species from other countries.

Resequencing of 410 Sesame Accessions Identifies SINST1 as the Major Underlying Gene for Lignans Variation.

Sesame is a promising oilseed crop that produces specific lignans of clinical importance. Hence, a molecular description of the regulatory mechanisms of lignan biosynthesis is essential for crop improvement. Here, we resequence 410 sesame accessions and identify 5.38 and 1.16 million SNPs (single nucleotide polymorphisms) and InDels, respectively. Population genomic analyses reveal that sesame has evolved a geographic pattern categorized into northern (NC), middle (MC), and southern (SC) groups, with potential origin in the southern region and subsequent introduction to the other regions. Selective sweeps analysis uncovers 120 and 75 significant selected genomic regions in MC and NC groups, respectively. By screening these genomic regions, we unveiled 184 common genes positively selected in these subpopulations for exploitation in sesame improvement. Genome-wide association study identifies 17 and 72 SNP loci for sesamin and sesamolin variation, respectively, and 11 candidate causative genes. The major pleiotropic SNPC/A locus for lignans variation is located in the exon of the gene SiNST1. Further analyses revealed that this locus was positively selected in higher lignan content sesame accessions, and the "C" allele is favorable for a higher accumulation of lignans. Overexpression of SiNST1C in sesame hairy roots significantly up-regulated the expression of SiMYB58, SiMYB209, SiMYB134, SiMYB276, and most of the monolignol biosynthetic genes. Consequently, the lignans content was significantly increased, and the lignin content was slightly increased. Our findings provide insights into lignans and lignin regulation in sesame and will facilitate molecular breeding of elite varieties and marker-traits association studies.

The anticancer peptide LL-III alters the physico-chemical properties of a model tumor membrane promoting lipid bilayer permeabilization.

LL-III is an anticancer peptide and has the ability to translocate across tumor cell membranes, which indicates that its action mechanism could be non-membranolytic. However, the exact mechanism through which the peptide gains access into the cell cytoplasm is still unknown. Here, we use a plethora of physico-chemical techniques to characterize the interaction of LL-III with liposomes mimicking the lipid matrix of the tumor cell membrane and its effect on the microstructure and thermotropic properties of the membrane. Furthermore, the effect of the presence of Ca2+ cations at physiological concentration was also investigated. For comparison, the interaction of LL-III with liposomes mimicking the normal cell membrane was also studied. Our results show that the peptide selectively interacts with the model tumor cell membrane. This interaction does not disrupt the lipid bilayer but deeply alters its properties by promoting lipid lateral reorganization and increasing membrane permeability. Overall, our data provide a molecular level description of the interaction of the peptide with the model tumor membrane and are fully consistent with the non-membranolytic action mechanism.

Application of functional proteomics in understanding RNA virus-mediated infection.

Together with the expansion of genome sequencing research, the number of protein sequences whose function is yet unknown is increasing dramatically. The primary goals of functional proteomics, a developing area of study in the realm of proteomic science, are the elucidation of the biological function of unidentified proteins and the molecular description of cellular systems at the molecular level. RNA viruses have emerged as the cause of several human infectious diseases with large morbidity and fatality rates. The introduction of high-throughput sequencing tools and genetic-based screening approaches over the last few decades has enabled researchers to find previously unknown and perplexing elements of RNA virus replication and pathogenesis on a scale never feasible before. Viruses, on the other hand, frequently disrupt cellular proteostasis, macromolecular complex architecture or stoichiometry, and post-translational changes to take over essential host activities. Because of these consequences, structural and global protein and proteoform monitoring is highly necessiated. Mass spectrometry (MS) has the potential to elucidate key details of virus-host interactions and speed up the identification of antiviral targets, giving precise data on the stoichiometry of cellular and viral protein complexes as well as mechanistic insights, has lately emerged as a key part of the RNA virus biology toolbox as a functional proteomics approach. Affinity-based techniques are primarily employed to identify interacting proteins in stable complexes in living organisms. A protein's biological role is strongly suggested by its relationship with other members of a certain protein complex that is involved in a particular process. With a particular emphasis on the most recent advancements in defining host responses and their translational implications to uncover novel tractable antiviral targets, this chapter provides insight on several functional proteomics techniques in RNA virus biology.

Insights into autoregulation of a membrane protein complex by its cytoplasmic domains

Membrane transporters mediate the passage of molecules across membranes and are essential for cellular function. While the transmembrane region of these proteins is responsible for substrate transport, often the cytoplasmic regions are required for modulating their activity. However, it can be difficult to obtain atomic-resolution descriptions of these autoregulatory domains by classical structural biology techniques, especially if they lack a single, defined structure. The betaine permease, BetP, a homotrimer, is a prominent and well-studied example of a membrane protein whose autoregulation depends on cytoplasmic N- and C-terminal segments. These domains sense and transduce changes in K+ concentration and in lipid bilayer properties caused by osmotic stress. However, structural data for these terminal domains is incomplete, which hinders a clear description of the molecular mechanism of autoregulation. Here we used microsecond-scale molecular simulations of the BetP trimer to compare reported conformations of the 45-amino-acid long C-terminal tails. The simulations provide support for the idea that the conformation derived from electron microscopy (EM) data represents a more stable global orientation of the C-terminal segment under downregulating conditions while also providing a detailed molecular description of its dynamics and highlighting specific interactions with lipids, ions, and neighboring transporter subunits. A missing piece of the molecular puzzle is the N-terminal segment, whose dynamic nature has prevented structural characterization. Using Rosetta to generate ensembles of de novo conformations in the context of the EM-derived structure robustly identifies two features of the N-terminal tail, namely 1) short helical elements and 2) an orientation that would confine potential interactions to the protomer in the counterclockwise direction (viewed from the cytoplasm). Since each C-terminal tail only contacts the protomer in the clockwise direction, these results indicate an intricate interplay between the three protomers of BetP in the downregulated protein and a multidirectionality that may facilitate autoregulation of transport.

Toward a general and interpretable umami taste predictor using a multi-objective machine learning approach

The umami taste is one of the five basic taste modalities normally linked to the protein content in food. The implementation of fast and cost-effective tools for the prediction of the umami taste of a molecule remains extremely interesting to understand the molecular basis of this taste and to effectively rationalise the production and consumption of specific foods and ingredients. However, the only examples of umami predictors available in the literature rely on the amino acid sequence of the analysed peptides, limiting the applicability of the models. In the present study, we developed a novel ML-based algorithm, named VirtuousUmami, able to predict the umami taste of a query compound starting from its SMILES representation, thus opening up the possibility of potentially using such a model on any database through a standard and more general molecular description. Herein, we have tested our model on five databases related to foods or natural compounds. The proposed tool will pave the way toward the rationalisation of the molecular features underlying the umami taste and toward the design of specific peptide-inspired compounds with specific taste properties.

Condensates formed by prion-like low-complexity domains have small-world network structures and interfaces defined by expanded conformations

Biomolecular condensates form via coupled associative and segregative phase transitions of multivalent associative macromolecules. Phase separation coupled to percolation is one example of such transitions. Here, we characterize molecular and mesoscale structural descriptions of condensates formed by intrinsically disordered prion-like low complexity domains (PLCDs). These systems conform to sticker-and-spacers architectures. Stickers are cohesive motifs that drive associative interactions through reversible crosslinking and spacers affect the cooperativity of crosslinking and overall macromolecular solubility. Our computations reproduce experimentally measured sequence-specific phase behaviors of PLCDs. Within simulated condensates, networks of reversible inter-sticker crosslinks organize PLCDs into small-world topologies. The overall dimensions of PLCDs vary with spatial location, being most expanded at and preferring to be oriented perpendicular to the interface. Our results demonstrate that even simple condensates with one type of macromolecule feature inhomogeneous spatial organizations of molecules and interfacial features that likely prime them for biochemical activity.

Production of Fluorescent Dissolved Organic Matter by Microalgae Strains from the Ob and Yenisei Gulfs (Siberia).

Dissolved organic matter (DOM) is an important component of aquatic environments; it plays a key role in the biogeochemical cycles of many chemical elements. Using excitation-emission matrix fluorescence spectroscopy, we examined the fluorescent fraction of DOM (FDOM) produced at the stationary phase of growth of five strains of microalgae sampled and isolated from the Ob and Yenisei gulfs. Based on the morphological and molecular descriptions, the strains were identified as diatoms (Asterionella formosa, Fragilaria cf. crotonensis, and Stephanodiscus hantzschii), green microalgae (Desmodesmus armatus), and yellow-green microalgae (Tribonema cf. minus). Three fluorescent components were validated in parallel factor analysis (PARAFAC): one of them was characterized by protein-like fluorescence (similar to peak T), two others, by humic-like fluorescence (peaks A and C). The portion of fluorescence intensity of humic compounds (peak A) to the total fluorescence intensity was the lowest (27 ± 5%) and showed little variation between species. Protein-like fluorescence was most intense (45 ± 16%), but along with humic-like fluorescence with emission maximum at 470 nm (28 ± 14%), varied considerably for different algae strains. The direct optical investigation of FDOM produced during the cultivation of the studied algae strains confirms the possibility of autochthonous production of humic-like FDOM in the Arctic shelf regions.

Two novel CHD7 variants in patients with typical and mild features of CHARGE syndrome co-occurring with esophageal atresia

CHARGE syndrome ( C oloboma, H eart defect, A tresia of the choanae, growth R etardation, G enital abnormalities, E ar anomalies/deafness) is a rare genetic autosomal dominant disease with a prevalence of 1/10,000 live births. It is associated with pathogenic variants in the chromodomain-helicase-DNA-binding protein 7 ( CHD7 ) gene. Although CHARGE syndrome is known to be associated with esophageal atresia (EA) and tracheoesophageal fistulas in 15–20% of cases, there are only a few clinical and molecular case descriptions of CHARGE syndrome in the context of EA. We present two individuals with novel CHD7 variants with variable clinical expression of CHARGE syndrome co-occurring with EA. Individual 1 had typical CHARGE syndrome, and a rare type D EA that required direct anastomosis repair. Genetic testing revealed a likely pathogenic essential splice site variant, c.4644+1G > T. Individual 2 had a mild CHARGE phenotype and a type A EA that required complex repair via the Foker process. The described expression of previously unreported typical CHD7 variants expands the current knowledge of CHARGE syndrome co-occurring with EA that could help with future patient care and genetic counseling. We hope that the description of the previously unreported variant of uncertain significance with a mild CHARGE phenotype will assist future classification efforts of this variant. • Novel report of two variants in CHD7 gene with wide clinical symptom variability. • Two clinical cases of CHARGE syndrome co-occurring with esophageal atresia. • Call to attention for genetic studies in infants born with esophageal atresia. • Call for innovations to public database of locus specific CHD7 variants.

Simulations and Experiments Reveal Diverse APOE States that Inform their Pathogenicity

AbstractBackgroundMutations to the lipid transport protein Apolipoprotein E (APOE) can dramatically increase the risk of developing late‐onset Alzheimer’s Disease (AD) by up to 15‐fold, however a molecular description of why some isoforms are protective while others are pathological has remained elusive. We hypothesize that individual APOE isoforms sample distinct conformational landscapes that are modulated by the presence of lipids, and that these landscapes contain co‐existing pathological and protective states.MethodTo test this hypothesis, we carried out a combination of molecular dynamics (MD) simulations and single‐molecule FRET (smFRET) experiments to highlight the conformational heterogeneity of human APOE isoforms, thereby informing states that differentially traffic lipids into neurons.ResultOur data suggests that there is no single pathological or protective APOE conformation, but rather a broad spectrum of protective and susceptible conformations that impact disease and memory impairment.ConclusionBiophysical studies are powerful tools that can inform the molecular mechanisms driving Alzheimer’s Disease and help bridge the gap between genetic associations (e.g. APOE status) and clinical phenotypes such as amyloid buildup or memory impairment.

A Core-Shell Approach for Systematically Coarsening Nanoparticle-Membrane Interactions: Application to Silver Nanoparticles.

The continuous release of engineered nanomaterial (ENM) into the environment may bring about health concerns following human exposure. One important source of ENMs are silver nanoparticles (NPs) that are extensively used as anti-bacterial additives. The introduction of ENMs into the human body can occur via ingestion, skin uptake or the respiratory system. Therefore, evaluating how NPs translocate over bio-membranes is essential in assessing their primary toxicity. Unfortunately, data regarding membrane-NP interaction is still scarce, as is theoretical and in silico insight into what governs adhesion and translocation for the most relevant NPs and membranes. Coarse-grained (CG) molecular descriptions have the potential to alleviate this situation, but are hampered by the absence of a direct link to NP materials and membrane adhesion mechanisms. Here, we interrogate the relationship between the most common NP representation at the CG level and the adhesion characteristics of a model lung membrane. We find that this representation for silver NPs is non-transferable, meaning that a proper CG representation for one size is not suited for other sizes. We also identify two basic types of primary adhesion-(partial) NPs wrapping by the membrane and NP insertion into the membrane-that closely relate to the overall NP hydrophobicity and significantly differ in terms of lipid coatings. The proven non-transferability of the standard CG representation with size forms an inspiration for introducing a core-shell model even for bare NPs that are uniform in composition. Using existing all-atom molecular dynamics (MD) data as a reference, we show that this extension does allow us to reproduce size-dependent NP adhesion properties and lipid responses to NP binding at the CG level. The subsequent CGMD evaluation for 10 nm Ag NPs provides new insight into membrane binding for relevant NP sizes and into the role of water in trapping NPs into defected mixed monolayer-bilayer states. This development will be instrumental for simulating NP-membrane adhesion towards more experimentally relevant length and time scales for particular NP materials.