Influence of nanopore coating patterns on the translocation dynamics of polyelectrolytes.

Polyelectrolytes can electrophoretically be driven through nanopores in order to be detected. The respective translocation events are often very fast and the process needs to be controlled to promote efficient detection. To this end, we attempt to control the translocation dynamics by coating the inner surface of a nanopore. For this, different charge distributions are chosen that result in substantial variations of the pore-polymer interactions. In addition and in view of the existing detection modalities, experimental settings, and nanopore materials, different types of sensors inside the nanopore have been considered to probe the translocation process and its temporal spread. The respective transport of polyelectrolytes through the coated nanopores is modeled through a multi-physics computational scheme that incorporates a mesoscopic/electrokinetic description for the solvent and particle-based scheme for the polymer. This investigation could underline the interplay between sensing modality, nanopore material, and detection accuracy. The electro-osmotic flow and electrophoretic motion in a pore are analyzed together with the polymeric temporal and spatial fluctuations unraveling their correlations and pathways to optimize the translocation speed and dynamics. Accordingly, this work sketches pathways in order to tune the pore-polymer interactions in order to control the translocation dynamics and, in the long run, errors in their measurements.

Electronic analysis of hydrogen-bonded molecular complexes: the case of DNA sensed in a functionalized nanogap.

DNA nucleotides can be interrogated by nanomaterials in order to be detected. With the aid of quantum-mechanical simulations, we unravel the intrinsic details of the electronic transport across nanoelectrodes functionalized with tiny modified diamond-like molecules. These electrodes generate a gap in which DNA nucleotides are placed and can be identified. The identification is strongly affected by the hydrogen bonding characteristics of the diamond-like particle and the nucleotides. The results point to the connection of the electronic transmission across the functionalized nanogap and the electronic and bonding characteristics of the molecular complexes within the nanogap. Specifically, our discussion focuses on the influence of the DNA dynamics on the electronic signals across the nanogap. We identify the molecular complex's details that hinder or promote the electronic transport through an analysis that moves from the bonding within the molecular complex up to the electronic current that this can accommodate. Accordingly, our work discusses pathways for analyzing hydrogen-bonded molecular complexes or molecules hydrogen-bonded to a material part having the optimization of the design of biosensing nanogaps and read-out nanopores in mind. The presented approach, though, is applicable to a wide range of applications utilizing exactly the bio/nano interface.

Functionalized electrodes embedded in nanopores: read-out enhancement?

In this review, functionalized nanogaps embedded in nanopores are discussed in view of their high biosensitivity in detecting biomolecules, their length, type, and sequence. Specific focus is given on nanoelectrodes functionalized with tiny nanometer-sized diamond-like particles offering vast functionalization possibilities for gold junction electrodes. This choice of the functionalization, in turn, offers nucleotide-specific binding possibilities improving the detection signals arising from such functionalized electrodes potentially embedded in a nanopore. The review sheds light onto the use and enhancement of the tunnelling recognition in functionalized nanogaps towards sensing DNA nucleotides and mutation detection, providing important input for a practical realization.

Probing the distribution of ionic liquid mixtures at charged and neutral interfaces via simulations and lattice-gas theory.

Room temperature ionic liquid solutions confined between neutral and charged surfaces are investigated by means of atomistic Molecular Dynamics simulations. We study 1-ethyl-3-methylimidazolium dicyanamide ([EMIm]+[DCA]-) in water or dimethylsulfoxide (DMSO) mixtures in confinement between two interfaces. The analysis is based on the comparison of the molecular species involved and the charged state of the surfaces. Focus is given on the influence of different water/DMSO concentrations on the microstructuring and accumulation of each species. Thermodynamic aspects, such as the entropic contributions in the observed trends are obtained from the simulations using a lattice-gas theory. The results clearly underline the differences in these properties for the water and DMSO mixtures and unravel the underlying mechanisms and inherent details. We were able to pinpoint the importance of the size and the relative permittivity of the molecules in guiding their microstructuring in the vicinity of the surfaces, as well as their interactions with the latter, i.e. the solute-surface interactions. The influence of water and DMSO on the overscreening at charged interfaces is also discussed. The analysis on the molecular accumulation at the interfaces allows us to predict whether the accumulation is entropy or enthalpy driven, which has an impact in the removal of the molecular species from the surfaces. We discuss the impact of this work in providing an essential understanding towards a careful design of electrochemical elements.

Simple Classification of RNA Sequences of Respiratory-Related Coronaviruses.

A very simple, fast, and efficient approach to analyze and identify respiratory-related virus sequences based on machine learning is proposed. Such schemes are very important in identifying viruses, especially in view of spreading pandemics. The method is based on genetic code rules and the open reading frame (ORF). Data from the respiratory-related coronaviruses are collected and features are extracted based on reoccurring nucleobase 3-tuples in the RNA. Our methodology is simply based on counting nucleobase triplets, normalizing the count to the length of the sequence, and applying principal component analysis (PCA) techniques. The triplet counting can be further used for classification purposes. DNA sequences from the herpes virus family can be considered as the first step towards a complete and accurate classification including more complex factors, such as mutations. The proposed classification scheme is simply based on "counting" biological information. It can serve as the first fast detection method, widely accessible and portable to a variety of distinct architectures for fast and on-the-fly detection. We provide an approach that can be further optimized and combined with supervised techniques to allow for more accurate detection and read out of the exact virus type or sequence. We discuss the relevance of this scheme in identifying differences in similar viruses and their impact on biochemical analysis.

Deep learning for nanopore ionic current blockades.

DNA molecules can electrophoretically be driven through a nanoscale opening in a material, giving rise to rich and measurable ionic current blockades. In this work, we train machine learning models on experimental ionic blockade data from DNA nucleotide translocation through 2D pores of different diameters. The aim of the resulting classification is to enhance the read-out efficiency of the nucleotide identity providing pathways toward error-free sequencing. We propose a novel method that at the same time reduces the current traces to a few physical descriptors and trains low-complexity models, thus reducing the dimensionality of the data. We describe each translocation event by four features including the height of the ionic current blockade. Training on these lower dimensional data and utilizing deep neural networks and convolutional neural networks, we can reach a high accuracy of up to 94% in average. Compared to more complex baseline models trained on the full ionic current traces, our model outperforms. Our findings clearly reveal that the use of the ionic blockade height as a feature together with a proper combination of neural networks, feature extraction, and representation provides a strong enhancement in the detection. Our work points to a possible step toward guiding the experiments to the number of events necessary for sequencing an unknown biopolymer in view of improving the biosensitivity of novel nanopore sequencers.

Adsorption of azide-functionalized thiol linkers on zinc oxide surfaces.

A comprehensive understanding of the interactions between organic molecules and a metal oxide surface is essential for an efficient surface modification and the formation of organic-inorganic hybrids with technological applications ranging from heterogeneous catalysis and biomedical templates up to functional nanoporous matrices. In this work, first-principles calculations supported by experiments are used to provide the microstructural characteristics of (101̄0) surfaces of zinc oxide single crystals modified by azide terminated hydrocarbons, which graft on the oxide through a thiol group. On the computational side, we evaluate the specific interactions between the surface and the molecules with the chemical formula N3(CH2) n SH, with n = 1, 3, 6, 9. We demonstrate that the molecules chemisorb on the bridge site of ZnO(101̄0). Upon adsorption, the N3(CH2) n SH molecules break the neutral (Zn δ+-O δ-) dimers on ZnO(101̄0) resulting in a structural distortion of the ZnO(101̄0) substrate. The energy decomposition analysis revealed that such structure distortion favors the adsorption of the molecules on the surface leading to a strong correlation between the surface distortion energy and the interaction energy of the molecule. An azide-terminated thiol with three methylene groups in the hydrocarbon chain N3(CH2)3SH was synthesized, and the assembly of this linker on ZnO surfaces was confirmed through atomic force microscopy. The bonding to the inorganic surface was examined via X-ray photoelectron spectroscopy (XPS). Clear signatures of the organic components on the oxide substrates were observed underlying the successful realization of thiol-grafting on the metal oxide. Temperature-dependent and angle-resolved XPS were applied to examine the thermal stability and to determine the thickness of the grafted SAMs, respectively. We discuss the high potential of our hybrid materials in providing further functionalities towards heterocatalysis and medical applications.

Electrically sensing Hachimoji DNA nucleotides through a hybrid graphene/h-BN nanopore.

The feasibility of synthesizing unnatural DNA/RNA has recently been demonstrated, giving rise to new perspectives and challenges in the emerging field of synthetic biology, DNA data storage, and even the search for extraterrestrial life in the universe. In line with this outstanding potential, solid-state nanopores have been extensively explored as promising candidates to pave the way for the next generation of label-free, fast, and low-cost DNA sequencing. In this work, we explore the sensitivity and selectivity of a graphene/h-BN based nanopore architecture towards detection and distinction of synthetic Hachimoji nucleobases. The study is based on a combination of density functional theory and the non-equilibrium Green's function formalism. Our findings show that the artificial nucleobases are weakly binding to the device, indicating a short residence time in the nanopore during translocation. Significant changes in the electron transmission properties of the device are noted depending on which artificial nucleobase resides in the nanopore, leading to a sensitivity in distinction of up to 80%. Our results thus indicate that the proposed nanopore device setup can qualitatively discriminate synthetic nucleobases, thereby opening up the feasibility of sequencing even unnatural DNA/RNA.

Functionalized Nanogap for DNA Read-Out: Nucleotide Rotation and Current-Voltage Curves.

Functionalized nanogaps embedded in nanopores show a strong potential for enhancing the detection of biomolecules, their length, type, and sequence. This detection is strongly dependent on the features of the target biomolecules, as well as the characteristics of the sensing device. In this work, through quantum-mechanical calculations, we elaborate on representative such aspects for the specific case of DNA detection and read-out. These aspects include the influence of single DNA nucleotide rotation within the nanogap and the current-voltage (I-V) characteristics of the nanogap. The results unveil a distinct variation in the electronic current across the functionalized device for the four natural DNA nucleotides with the applied voltage. These also underline the asymmetric response of the rotating nucleotides on this applied voltage and the respective variation in the rectification ratio of the device. The electronic tunneling current across the nanogap can be further enhanced through the proper choice of an applied bias voltage. We were able to correlate the enhancement of this current to the nucleotide rotation dynamics and a shift of the electronic transmission peaks towards the Fermi level. This nucleotide specific shift further reveals the sensitivity of the device in reading-out the identity of the DNA nucleotides for all different configurations in the nanogap. We underline the important information that can be obtained from both the I-V curves and the rectification characteristics of the nanogap device in view of accurately reading-out the DNA information. We show that tuning the applied bias can enhance this detection and discuss the implications in view of novel functionalized nanopore sequencers.

The influence of a solvent on the electronic transport across diamondoid-functionalized biosensing electrodes.

Electrodes embedded in nanopores have the potential to detect the identity of biomolecules, such as DNA. This identification is typically being done through electronic current measurements across the electrodes in a solvent. In this work, using quantum-mechanical calculations, we qualitatively present the influence of this solvent on the current signals. For this, we model electrodes functionalized with a small diamond-like molecule known as diamondoid and place a DNA nucleotide within the electrode gap. The influence of an aqueous solvent is taken explicitly into account through Quantum-Mechanics/Molecular Mechanics (QM/MM) simulations. From these, we could clearly reveal that at the (111) surface of the Au electrode, water molecules form an adlayer-like structure through hydrogen bond networks. From the temporal evolution of the hydrogen bond between a nucleotide and the functionalizing diamondoid, we could extract information on the conductance across the device. In order to evaluate the influence of the solvent, we compare these results with ground-state electronic structure calculations in combination with the non-equilibrium Green's function (NEGF) approach. These allow access to the electronic transport across the electrodes and show a difference in the detection signals with and without the aqueous solution. We analyze the results with respect to the density of states in the device. In the end, we demonstrate that the presence of water does not hinder the detection of a mutation over a healthy DNA nucleotide. We discuss these results in view of sequencing DNA with nanopores.

In silico Complexes of Amino Acids and Diamondoids.

We report on the specific interaction of a small diamond-like molecule, known as diamondoid, with single amino-acids forming nano/bio molecular complexes. Using time-dependent density-functional theory calculations we have studied two different relative configurations of three prototypical amino acids, phenylalanine, tyrosine, and tryptophan, with the diamondoid. The optical and charge-transfer properties of these complexes exhibit amino acid and topology specific features which can be directly utilized for in the direction of novel biomolecule detection schemes.

Hybrids made of defective nanodiamonds interacting with DNA nucleobases.

The characteristics of hybrids made of a defective nanodiamond and a biomolecule unit are investigated in this work. Focus is given on the interaction between the nanodiamond and a DNA nucleobase. The latter is placed close to the former in two different arrangements, realizing different bonding types. The nanodiamond includes a negatively charged nitrogen-vacancy center and is hydrogen terminated. Using quantum-mechanical calculations, we could elucidate the structural and electronic properties of such hybrids. Our study clearly identifies the importance of the relative orientation of the two components, the nanodiamond and the nucleobase, in the complex in controlling the electronic properties of the resulting hybrid. The position of the defect at the center or closer to its interface with the nucleobase further controls the electronic orbitals around the defect center, hence its optical activity. In the end, we discuss the relevance of our work in biosensing.

Coarse-Grained Double-Stranded RNA Model from Quantum-Mechanical Calculations.

A coarse-grained model for simulating structural properties of double-stranded RNA is developed with parameters obtained from quantum-mechanical calculations. This model follows previous parametrization for double-stranded DNA, which is based on mapping the all-atom picture to a coarse-grained four-bead scheme. Chemical and structural differences between RNA and DNA have been taken into account for the model development. The parametrization is based on simulations using density functional theory (DFT) on separate units of the RNA molecule without implementing experimental data. The total energy is decomposed into four terms of physical significance: hydrogen bonding interaction, stacking interactions, backbone interactions, and electrostatic interactions. The first three interactions are treated within DFT, whereas the last one is included within a mean field approximation. Our double-stranded RNA coarse-grained model predicts stable helical structures for RNA. Other characteristics, such as structural or mechanical properties are reproduced with a very good accuracy. The development of the coarse-grained model for RNA allows extending the spatial and temporal length scales accessed by computer simulations and being able to model RNA-related biophysical processes, as well as novel RNA nanostructures.

Optical Properties of Single- and Double-Functionalized Small Diamondoids.

The rational control of the electronic and optical properties of small functionalized diamond-like molecules, the diamondoids, is the focus of this work. Specifically, we investigate the single- and double- functionalization of the lower diamondoids, adamantane, diamantane, and triamantane with -NH2 and -SH groups and extend the study to N-heterocyclic carbene (NHC) functionalization. On the basis of electronic structure calculations, we predict a significant change in the optical properties of these functionalized diamondoids. Our computations reveal that -NH2 functionalized diamondoids show UV photoluminescence similar to ideal diamondoids while -SH substituted diamondoids hinder the UV photoluminescence due to the labile nature of the S-H bond in the first excited state. This study also unveils that the UV photoluminescence nature of -NH2 diamondoids is quenched upon additional functionalization with the -SH group. The double-functionalized derivative can, thus, serve as a sensitive probe for biomolecule binding and sensing environmental changes. The preserved intrinsic properties of the NHC and the ideal diamondoid in NHC-functionalized-diamondoids suggests its utilization in diamondoid-based self-assembled monolayers (SAM), whose UV-photoluminescent signal would be determined entirely by the functionalized diamondoids. Our study aims to pave the path for tuning the properties of diamondoids through a selective choice of the type and number of functional groups. This will aid the realization of optoelectronic devices involving, for example, large-area SAM layers or diamondoid-functionalized electrodes.

Electrokinetic Lattice Boltzmann Solver Coupled to Molecular Dynamics: Application to Polymer Translocation.

We have developed a theoretical and computational approach to deal with systems that involve a disparate range of spatiotemporal scales, such as those composed of colloidal particles or polymers moving in a fluidic molecular environment. Our approach is based on a multiscale modeling that combines the slow dynamics of the large particles with the fast dynamics of the solvent into a unique framework. The former is numerically solved via Molecular Dynamics and the latter via a multicomponent Lattice Boltzmann. The two techniques are coupled together to allow for a seamless exchange of information between the descriptions. Being based on a kinetic multicomponent description of the fluid species, the scheme is flexible in modeling charge flow within complex geometries and ranging from large to vanishing salt concentration. The details of the scheme are presented and the method is applied to the problem of translocation of a charged polymer through a nanopores. Lastly, we discuss the advantages and complexities of the approach.

The properties of residual water molecules in ionic liquids: a comparison between direct and inverse Kirkwood-Buff approaches.

We study the properties of residual water molecules at different mole fractions in dialkylimidazolium based ionic liquids (ILs), namely 1-ethyl-3-methylimidazolium tetrafluoroborate (EMIM/BF4) and 1-butyl-3-methylimidazolium tetrafluoroborate (BMIM/BF4) by means of atomistic molecular dynamics (MD) simulations. The corresponding Kirkwood-Buff (KB) integrals for the water-ion and ion-ion correlation behavior are calculated by a direct evaluation of the radial distribution functions. The outcomes are compared to the corresponding KB integrals derived by an inverse approach based on experimental data. Our results reveal a quantitative agreement between both approaches, which paves a way towards a more reliable comparison between simulation and experimental results. The simulation outcomes further highlight that water even at intermediate mole fractions has a negligible influence on the ion distribution in the solution. More detailed analysis on the local/bulk partition coefficients and the partial structure factors reveal that water molecules at low mole fractions mainly remain in the monomeric state. A non-linear increase of higher order water clusters can be found at larger water concentrations. For both ILs, a more pronounced water coordination around the cations when compared to the anions can be observed, which points out that the IL cations are mainly responsible for water pairing mechanisms. Our simulations thus provide detailed insights in the properties of dialkylimidazolium based ILs and their effects on water binding.

Diamondoid-based molecular junctions: a computational study.

In this work, we deal with the computational investigation of diamondoid-based molecular conductance junctions and their electronic transport properties. A small diamondoid is placed between the two gold electrodes of the nanogap and is covalently bonded to the gold electrodes through two different molecules, a thiol group and a N-heterocyclic carbene molecule. We have shown that the thiol linker is more efficient as it introduces additional electron paths for transport at lower energies. The influence of doping the diamondoid on the properties of the molecular junctions has been investigated. We find that using a nitrogen atom to dope the diamondoids leads to a considerable increase of the zero bias conductance. For the N-doped system we show an asymmetric feature of the I-V curve of the junctions resulting in rectification within a very small range of bias voltages. The rectifying nature is the result of the characteristic shift in the bias-dependent highest occupied molecular orbital state. In all cases, the efficiency of the device is manifested and is discussed in view of novel nanotechnological applications.

Benchmark investigation of diamondoid-functionalized electrodes for nanopore DNA sequencing.

Small diamond-like particles, diamondoids, have been shown to effectively functionalize gold electrodes in order to sense DNA units passing between the nanopore-embedded electrodes. In this work, we present a comparative study of Au(111) electrodes functionalized with different derivatives of lower diamondoids. Focus is put on the electronic and transport properties of such electrodes for different DNA nucleotides placed within the electrode gap. The functionalization promotes a specific binding to DNA leading to different properties for the system, which provides a tool set to systematically improve the signal-to-noise ratio of the electronic measurements across the electrodes. Using quantum transport calculations, we compare the effectiveness of the different functionalized electrodes in distinguishing the four DNA nucleotides. Our results point to the most effective diamondoid functionalization of gold electrodes in view of biosensing applications.

Binding energies of nucleobase complexes: Relevance to homology recognition of DNA.

The binding energies of complexes of DNA nucleobase pairs are evaluated using quantum mechanical calculations at the level of dispersion corrected density functional theory. We begin with Watson-Crick base pairs of singlets, duplets, and triplets and calculate their binding energies. At a second step, mismatches are incorporated into the Watson-Crick complexes in order to evaluate the variation in the binding energy with respect to the canonical Watson-Crick pairs. A linear variation of this binding energy with the degree of mismatching is observed. The binding energies for the duplets and triplets containing mismatches are further compared to the energies of the respective singlets in order to assess the degree of collectivity in these complexes. This study also suggests that mismatches do not considerably affect the energetics of canonical base pairs. Our work is highly relevant to the recognition process in DNA promoted through the RecA protein and suggests a clear distinction between recognition in singlets, and recognition in duplets or triplets. Our work assesses the importance of collectivity in the homology recognition of DNA.

Carbene-mediated self-assembly of diamondoids on metal surfaces.

N-heterocyclic carbenes (NHC)s are emerging as an alternative class of molecules to thiol-based self-assembled monolayers (SAMs), making carbene-based SAMs much more stable under harsh environmental conditions. In this work, we have functionalized tiny diamondoids using NHCs in order to prepare highly stable carbene-mediated diamondoid SAMs on metal substrates. Using quantum-mechanical simulations and two different configurations for the carbene-functionalized diamondoids attached on gold, silver, and platinum surfaces we were able to study in detail these materials. Specifically, we focus on the binding characteristics, stability, and adsorption of the NHC-mediated diamondoid SAMs on the metal surfaces. A preferential binding to platinum surfaces was found, while a modulation of the work function in all cases was clear. The surface morphology of all NHC-based diamondoid SAMs was revealed through simulated STM images, which show characteristic features for each surface.