Caging Polycations: Effect of Increasing Confinement on the Modes of Interaction of Spermidine3+ With DNA Double Helices

Polyamines have important roles in the modulation of the cellular function and are ubiquitous in cells. The polyamines putrescine2+, spermidine3+, and spermine4+ represent the most abundant organic counterions of the negatively charged DNA in the cellular nucleus. These polyamines are known to stabilize the DNA structure and, depending on their concentration and additional salt composition, to induce DNA aggregation, which is often referred to as condensation. However, the modes of interactions of these elongated polycations with DNA and how they promote condensation are still not clear. In the present work, atomistic molecular dynamics (MD) computer simulations of two DNA fragments surrounded by spermidine3+ (Spd3+) cations were performed to study the structuring of Spd3+ “caged” between DNA molecules. Microsecond time scale simulations, in which the parallel DNA fragments were constrained at three different separations, but allowed to rotate axially and move naturally, provided information on the conformations and relative orientations of surrounding Spm3+ cations as a function of DNA-DNA separation. Novel geometric criteria allowed for the classification of DNA-Spd3+ interaction modes, with special attention given to Spd3+ conformational changes in the space between the two DNA molecules (caged Spd3+). This work shows how changes in the accessible space, or confinement, around DNA affect DNA-Spd3+ interactions, information fundamental to understanding the interactions between DNA and its counterions in environments where DNA is compacted, e.g. in the cellular nucleus

MD simulations explain the excess molar enthalpies in pseudo-binary mixtures of a choline chloride-based deep eutectic solvent with water or methanol

The addition of molecular liquid cosolvents to choline chloride (ChCl)-based deep eutectic solvents (DESs) is increasingly investigated for reducing the inherently high bulk viscosities of the latter, which represent a major obstacle for potential industrial applications. The molar enthalpy of mixing, often referred to as excess molar enthalpy H E-a property reflecting changes in intermolecular interactions upon mixing-of the well-known ChCl/ethylene glycol (1:2 molar ratio) DES mixed with either water or methanol was recently found to be of opposite sign at 308.15 K: Mixing of the DES with water is strongly exothermic, while methanol mixtures are endothermic over the entire mixture composition range. Knowledge of molecular-level liquid structural changes in the DES following cosolvent addition is expected to be important when selecting such "pseudo-binary" mixtures for specific applications, e.g., solvents. With the aim of understanding the reason for the different behavior of selected DES/water or methanol mixtures, we performed classical MD computer simulations to study the changes in intermolecular interactions thought to be responsible for the observed H E sign difference. Excess molar enthalpies computed from our simulations reproduce, for the first time, the experimental sign difference and composition dependence of the property. We performed a structural analysis of simulation configurations, revealing an intriguing difference in the interaction modes of the two cosolvents with the DES chloride anion: water molecules insert between neighboring chloride anions, forming ionic hydrogen-bonded bridges that draw the anions closer, whereas dilution of the DES with methanol results in increased interionic separation. Moreover, the simulated DES/water mixtures were found to contain extended hydrogen-bonded structures containing water-bridged chloride pair arrangements, the presence of which may have important implications for solvent applications

Theoretical and Experimental Study of the Excess Thermodynamic Properties of Highly Nonideal Liquid Mixtures of Butanol Isomers + DBE

Binary alcohol + ether liquid mixtures are of significant importance as potential biofuels or additives for internal combustion engines and attract considerable fundamental interest as model systems containing one strongly H-bonded self-associating component (alcohol) and one that is unable to do so (ether), but that can interact strongly as a H-bond acceptor. In this context, the excess thermodynamic properties of these mixtures, specifically the excess molar enthalpies and volumes (HE and VE), have been extensively measured. Butanol isomer + di-n-butyl ether (DBE) mixtures received significant attention because of interesting differences in their VE, changing from negative (1- and isobutanol) to positive (2- and tert-butanol) with increasing alkyl group branching. With the aim of shedding light on the differences in alcohol self-association and cross-species H-bonding, considered responsible for the observed differences, we studied representative 1- and 2-butanol + DBE mixtures by molecular dynamics simulations and experimental excess property measurements. The simulations reveal marked differences in the self-association of the two isomers and, while supporting the existing interpretations of the HE and VE in a general sense, our results suggest, for the first time, that subtle changes in H-bonded topologies may contribute significantly to the anomalous volumetric properties of these mixtures

Carbon Nanodots from an In Silico Perspective

Carbon nanodots (CNDs) are the latest and most shining rising stars among photoluminescent (PL) nanomaterials. These carbon-based surface-passivated nanostructures compete with other related PL materials, including traditional semiconductor quantum dots and organic dyes, with a long list of benefits and emerging applications. Advantages of CNDs include tunable inherent optical properties and high photostability, rich possibilities for surface functionalization and doping, dispersibility, low toxicity, and viable synthesis (top-down and bottom-up) from organic materials. CNDs can be applied to biomedicine including imaging and sensing, drug-delivery, photodynamic therapy, photocatalysis but also to energy harvesting in solar cells and as LEDs. More applications are reported continuously, making this already a research field of its own. Understanding of the properties of CNDs requires one to go to the levels of electrons, atoms, molecules, and nanostructures at different scales using modern molecular modeling and to correlate it tightly with experiments. This review highlights different in silico techniques and studies, from quantum chemistry to the mesoscale, with particular reference to carbon nanodots, carbonaceous nanoparticles whose structural and photophysical properties are not fully elucidated. The role of experimental investigation is also presented. Hereby, we hope to encourage the reader to investigate CNDs and to apply virtual chemistry to obtain further insights needed to customize these amazing systems for novel prospective applications

Cholinium-Based Ionic Liquids from Hydroxycinnamic Acids as New Promising Bioactive Agents: A Combined Experimental and Theoretical Investigation

Cholinium-based ionic liquids (Cho-ILs) are very attractive compounds for medicinal and pharmaceutical applications as bioavailability enhancers in drug formulations and active components in pharmaceutical ingredients. In this study, we synthesized six Cho-ILs from hydroxycinnamic acids (HCA) ([Cho][HCA] ILs), a group of bioactive compounds with poor water solubility. [Cho][HCA] ILs and their parent acids were evaluated for solubility, thermal stability, and antioxidant activity. Furthermore, [Cho][HCA] ILs were screened for their cytotoxicity. To rationalize the experimental antioxidant activities, density functional theory (DFT) calculations were performed. The theoretical approach allowed for identification of the most likely radical scavenging mechanisms involving HCAs and the corresponding ionic forms under the studied experimental conditions and to rationalize the observed activity differences between salts and acids. Overall, our results revealed a higher solubility and free-radical scavenging activity for [Cho][HCA] ILs than corresponding HCAs, a relatively high thermal stability (melting temperature > 100 °C) and negligible cytotoxicity activity. Furthermore, DFT calculations showed that both the hydrogen atom transfer and the sequential proton loss electron transfer mechanisms are likely to occur in aqueous and ethanolic solutions. The picture emerging from our results supports the increasingly expressed idea that [Cho][HCA]ILs are promising candidates for applications in pharmaceutical formulatio

Computer simulation studies of micro-heterogeneous liquid mixtures

Liquid mixtures are part of our everyday lives and are important in numerous chemical research and industrial applications. While often apparently featureless, uniform and uninteresting, kept in bottles and containers in the chemical laboratory, their molecular-level structure and physical properties can be completely the opposite, and are continually attracting scientific interest. Strong repulsive and attractive interactions between the molecules can create most intriguing local arrangements, molecular aggregates and complexes, whose spatial organisation is often difficult to characterise, or rationalise. Moreover, the same liquid components can behave completely differently depending on the mixing ratio, strongly affecting macroscopic properties, e.g. mass density, viscosity or melting/boiling points. To gain insight into the complex world of binary liquid mixtures, deep eutectic solvents and ionic liquids, a combination of experimental and theoretical, or computational, studies is necessary. In this thesis, the focus is on understanding how the microscopic molecular organization in organic solvent mixtures affects the physico-chemical and solvating properties. While in all of the presented studies the systems are investigated both experimentally and computationally, the main focus of my thesis is on computational modelling, primarily based on molecular mechanics. In this approach, the system of interest is modelled by interacting particles representing either single atoms of groups of atoms, and their interactions and movements are described by classical mechanics. This approximate method allows for the modelling of large molecular systems, e.g. liquid mixtures with structural heterogeneities on the nanometer length scale and microsecond time scale. Specifically, my work has been devoted to the following problems: (1) Explaining how large anions in mixed liquid solvents can be apparently preferentially solvated by the less polar components, described in Chapter 3. (2) Explaining excess thermodynamics properties for relatively simple organic solvent liquid mixtures, described in Chapter 4, and extending the investigation approach to more complex “pseudo-binary” mixtures of DES with water or methanol, where it has not been applied before, described in Chapter 6. (3) Developing coarse-grained models of charged liquid solvent, to be able to verify the long-range ordering effects connected to solvent micro-segregation, described in Chapter 5. The fundamental concepts and background are provided in Chapter 1 & 2

A 195Pt Nuclear magnetic resonance and molecular dynamics computer simulation study of the solvation of simple platinum (IV) chlorido complex anions in water and water-miscible solvent mixtures

Thesis (PhD)--Stellenbosch University, 2017.ENGLISH ABSTRACT: A combined 195Pt NMR spectroscopy and Molecular Dynamics (MD) computer simulation study of the solvation of the octahedral Pt(IV) complex [PtCl6]2‒ in binary mixtures of water and the fully water-miscible organic solvents methanol, 2-methoxyethanol and 1,2-dimethoxyethane has been carried out. A recent 195Pt NMR chemical shift-trends study indicated a preferential solvation of the aforementioned platinum complex by the organic solvent component in such solvent mixtures. The solvent dependence of the intrinsic 1Δ195Pt(37/35Cl) NMR isotope shifts of [PtCl6]2‒ in pure solvents indicate a slight increase in magnitude ~7 ppb in the order water Cl‒ > H2O in aqueous solution.AFRIKAANSE OPSOMMING: ʼn Gekombineerde 195Pt KMR spektroskopie en Molekulêre Dinamika (MD) rekenaar-simulasie studie van die solvasie van die oktahedriese Pt(IV) kompleks [PtCl6]2‒ in binêre mengsels van water en volledig water mengbare organiese oplosmiddels metanol, 2-metoksiëtanol en 1,2-dimetoksiëtaan is uitgevoer. ʼn Onlangse studie van 195Pt KMR chemiese verskuiwings (frekwensies) het ʼn voorkeur solvasie vir solvasie van die platinum kompleks deur die organiese komponent in sulke mengsels aangedui. Die 1Δ195Pt(37/35Cl) KMR isotoopverskuiwing van [PtCl6]2‒ in suiwer oplosmiddels toon ʼn relatief klein toename van ~7 ppb in die orde van oplosmiddels, water < metanol < 2-metoksiëtanol < 1,2-dimetoksiëtaan. Die 1Δ195Pt(37/35Cl) verskuiwing gemeet in sekere ekwimolare binêre mengsels van water en organiese oplosmiddels is soortgelyk in grootte aan die verskuiwing in die suiwer organiese oplosmiddel, in ooreenkoms met die voorgestelde voorkeur vir die organiese komponent. 195Pt KMR T1 kenmerkende tye en translasionele diffusiekoëffisiente m.b.v. die gepulsde gradient spin-echo (PGSE) tegniek, is ook gemeet vir [PtCl6]2‒ in geselekteerde oplosmiddels en binêre mengsels. Die resultate word geïnterpreteer in die konteks van hidrodinamiese modelle van molekulêre diffusie, en alhowel daar gevind word dat sulke modelle nie geskik is vir hierdie doel, word getoon dat die resultate nietemin algemeen konsistent is met die voorgestelde oplosmiddelvoorkeur, soos aangedui. ʼn Reeks klassieke MD rekenaarsimulasies van [PtCl6]2‒ in binêre oplosmiddelmengsels is uitgevoer deur gebruik te maak van ʼn onlangs-hersiende model wat deur Naidoo et al. ontwikkel is. Die resultate van simulasies, wat met die standaard model vir die platinum kompleks uitgevoer is, toon ʼn sterk voorkeur vir water in die onmiddelike omgewing van die kompleks in alle gebestudeerde mengsels. ʼn Soortgelyke resultaat is verkry vir die vierkantig-planêre [PtCl4]2‒ in ʼn ekwimolare water‒metanol mengsel. Die simulasies is herhaal deur ioniese ladings aan te pas volgens die onlangs ontwikkelde Molekulêre Dinamika in Elektroniese Kontinuum (MDEK, oorspronklik MDEC) teorie, wat deels voosiening maak vir die diëlektriese afskerming van gelaaide partikels in gekondenseerde fases. In hiedie MDEK simulasies word ʼn merkbare afname in die bydrae deur water tot die primêre oplosmiddel omgewing van beide komplekse waargeneem: die effek is veral ooglopend in die geval van [PtCl6]2‒ in mengels van water met 2- metoksiëtanol en 1,2-dimetoksiëtaan, waarin ʼn sterk voorkeur vir die organiese komponent eksperimenteel waargeneem is. Dinamiese einskappe is ook van MD trajekte bereken, en toon tendense soortgelyk aan eksperimentele waardes, maar wyk af weens die oplosmiddelmodel. Verder is ʼn interpretasie van die fassinerende 35/37Cl en 16/18O isotoopgeïndusseerde fynstruktuur in die 195Pt KMR spektra van komplekse met vorm [PtCln(OH)6‒n]2‒, n = 0‒5, voorgestel, gebasseer op die verwagte trans-invloedreeks van ligande vir Pt(IV) H2O < Cl‒ < OH‒ in waterige oplossing

A study of isotope-effects in the high-resolution 195Pt NMR spectra of octahedral complexes of the type [PtCl6-n(OH)n]2-, n = 0-6, in water

Thesis (MSc)--Stellenbosch University, 2013.ENGLISH ABSTRACT: The high-resolution 195Pt NMR signals (128.8 MHz) of most of the octahedral mixed-ligand Pt(IV) complexes in the series [PtCl6-n(OH)n]2-, n = 0-6, have been recorded in aqueous solutions at 293 K. These signals show characteristic 35/37Cl isotope-induced fine structure that results from the presence of several isotopologues in samples with a natural chlorine isotope distribution; each 37Cl isotope incorporated into the Pt coordination sphere of one of these complexes affords a fixed upfield (low frequency) isotope shift of between 0.17 and 0.22 ppm, depending on the particular complex. This assignment is confirmed by the excellent agreement between the natural abundances of the various isotopologues and the relative contributions of the corresponding signals to the overall area of the experimental spectrum of the particular isotoplogue set, obtained by a non-linear least-squares line fitting procedure. These results confirm that the 195Pt magnetic shielding in isotopomers differing only in the combination of the two chlorine isotopes coordinated in sites trans to hydroxido-ligands are indistinguishable under these experimental conditions, unlike those of similar isotopomers in the related series of aqua-complexes [PtCln(H2O)6-n]4-n, n = 3-5, as reported by Koch and co-workers. Moreover, the order of 195Pt shielding for the members of all stereoisomer pairs in the series of hydroxido-complexes is the reverse of that reported for the corresponding pairs in the aqua-series. These and other observations are interpreted qualitatively in terms of the relative strengths of the trans-influences of aqua-, hydroxido- and chlorido-ligands and the effect of these on bond displacements in these complexes. The 195Pt NMR spectra of especially the complexes cis-[PtCl2(OH)4]2- and [PtCl(OH)5]2- show remarkable fine structure in a ca. 45 % 18O-enriched aqueous solution; apart from additional signals resulting from 18O-containing isotopologues, the resonance signals of isotopomers differing in the combination of 16/18O isotopes in sites trans to chlorido-ligands are partially resolved. The effect of temperature on the 35/37Cl isotope-induced fine structure in the 195Pt signals of [PtCl6]2- and [PtCl(OH)5]2- was investigated in the range 283-308 K; some interesting differences are observed. 195Pt relaxation time measurements for [PtCl6]2- in this temperature range reveal that line-broadening is at least partially responsible for the loss of resolution between the signals of isotopologues of this complex as the temperature is increased, possibly due to the spin-rotation relaxation mechanism. The temperature coefficient of 195Pt shielding and the magnitude of isotope shifts in the spectra of the complexes in this series show interesting correlations with the 195Pt shielding itself; an interpretation of these observations is presented.AFRIKAANSE OPSOMMING: Die hoëresolusie 195Pt NMR seine (128.8 MHz) van die oktaëdriese gemengde-ligand Pt(IV) komplekse in die reeks [PtCl6-n(OH)n]2- is waargeneem in waterige oplossing by ʼn temperatuur van 293 K. Hierdie seine toon ʼn karakteristieke 35/37Cl isotoop-geïnduseerde fynstruktuur as gevolg van die teenwoordigheid van verskeie isotopoloë in monsters met ʼn natuurlike chloor isotoopverspreiding. Die verplasing van ʼn 35Cl isotoop deur ʼn 37Cl isotoop in die Pt koördinasiesfeer van hierdie komplekse lei tot ʼn laefrekwensie isotoopverskuiwing van die 195Pt resonansiesein van tussen 0.17 en 0.22 ppm, afhangend van die spesifieke kompleks. Die toekenning van resonansieseine in hierdie spektra word ondersteun deur die goeie ooreenstemming tussen die berekende natuurlike verspreiding van isotopoloë en die persentasie area bydrae van die ooreenstemmende pieke tot die area van volledige stel seine van die chemiese spesie, soos bepaal deur ʼn nie-linieêre kleinste-kwadrate passingsmetode. Hierdie resultate bevestig dat vir isotopomere waarvan slegs die kombinasie van chloorisotope wat in posisies trans tot hidroksido-ligande gekoördineer is ʼn ononderskeibare 195Pt magnetiese skerming waargeneem word, m.a.w. ʼn enkele resonansiesein word vir hierdie isotopomere gemeet, anders as gerapporteer deur Koch en medewerkers vir die verwante aqua-komplekse [PtCln(H2O)6-n]4-n waar n = 3-5. Verder is die order van 195Pt magnetiese skerming vir stereoisomere in hierdie hidroksido-komplekse in elke stereoisomer paar die teenoorgestelde van dit waargeneem vir die ooreenstemmende aqua-komplekse. Hierdie waarnemings word kwalitatief geïnterpreteer in terme van die verskillende trans-invloede van die chlorido-, aqua- en hidroksido-ligande en die effekte daarvan op bindingslengtes in die komplekse. In ʼn ongeveer 45 % 18O-verrykte monster toon die 195Pt seine van veral die komplekse cis-[PtCl2(OH)4]2- en [PtCl(OH)5]2- uitsonderlike fynstruktuur vanweë die addisionele seine van 18O-bevattende isotopoloë en die parsiële resolusie van die seine van isotopomere wat verskil in die kombinasie van 16/18O isotope wat trans tot chlorido-ligande gekoördineer is. ʼn Studie is gemaak van die uitwerking van temperatuur op die 35/37Cl isotoop-geïnduseerde fynstruktuur in die 195Pt seine van die komplekse [PtCl6]2- en [PtCl(OH)5]2- in die gebied 283-308 K; interessante verskille is waargeneem. 195Pt magnetiese relaksasietyd metings vir die kompleks [PtCl6]2- in waterige oplossing in hierdie temperatuurgebied toon dat verbreeding van resonansieseine ten minste gedeeltelik verantwoordelik is vir die waargenome verlies aan resolusie tussen die seine van isotopoloë namate die temperatuur styg; die verbreeding van seine kan waarskynlik aan die spin-rotasie relaksasiemeganisme toegeskryf word. Die temperatuurkoëffisiënt van 195Pt magnetiese skerming en die grootheid van isotoopverskuiwings in die spektra van die hidroksido-komplekse in hierdie reeks toon interessante korrelasies tot die 195Pt magnetiese skerming; ʼn interpretasie van hierdie waarnemings word voorgestel

195Pt NMR and Molecular Dynamics Simulation Study of the Solvation of [PtCl6]2-in Water-Methanol and Water-Dimethoxyethane Binary Mixtures

The experimental195Pt NMR chemical shift, δ(195Pt), of the [PtCl6]2-anion dissolved in binary mixtures of water and a fully miscible organic solvent is extremely sensitive to the composition of the mixture at room temperature. Significantly nonlinear δ(195Pt) trends as a function of solvent composition are observed in mixtures of water-methanol, or ethylene glycol, 2-methoxyethanol, and 1,2-dimethoxyethane (DME). The extent of the deviation from linearity of the δ(195Pt) trend depends strongly on the nature of the organic component in these solutions, which broadly suggests preferential solvation of the [PtCl6]2-anion by the organic molecule. This simplistic interpretation is based on an accepted view pertaining to monovalent cations in similar binary solvent mixtures. To elucidate these phenomena in detail, classical molecular dynamics computer simulations were performed for [PtCl6]2-in water-methanol and water-DME mixtures using the anionic charge scaling approach to account for the effect of electronic dielectric screening. Our simulations suggest that the simplistic model of preferential solvation of [PtCl6]2-by the organic component as inferred from nonlinear δ(195Pt) trends is not entirely accurate, particularly for water-DME mixtures. The δ(195Pt) trend in these mixtures levels off for high DME mole fractions, which results from apparent preferential location of [PtCl6]2-anions at the borders of water-rich regions or clusters within these inherently micro-heterogeneous mixtures. By contrast in water-methanol mixtures, apparently less pronounced mixed solvent micro-heterogeneity is found, suggesting the experimental δ(195Pt) trend is consistent with a more moderate preferential solvation of [PtCl6]2-anions. This finding underlines the important role of solvent-solvent interactions and micro-heterogeneity in determining the solvation environment of [PtCl6]2-anions in binary solvent mixtures, probed by highly sensitive195Pt NMR. The notion that preferential solvation of [PtCl6]2-results primarily from competing ion-solvent interactions as generally assumed for monatomic ions, may not be appropriate in general

Unusual bending patterns of spermidine3+ bound to DNA double helix

Natural polyamines play a fundamental role in the cell cycle. Despite being recognized as the most abundant organic counterions of DNA in the cell nucleus, their interactions with DNA have not been fully characterized. In a recent work [S. Perepelytsya, T. Vasiliu, A. Laaksonen, L. Engelbrecht, G. Brancato, and F. Mocci, J. Molec. Liq. 389, 122828 (2023)], we have shown how the interactions between spermidine(3+) and the DNA double helix induce significant conformational variations in the polyamine molecule. Specifically, we found that DNA induces conformations that are not observed in solution. Following that study, we present here a detailed investigation of the most compact conformation of the polyamine, analyzing its connection to the interaction with the DNA duplex. The analysis reveals that anomalous bent conformations of the spermidine(3+) molecule result from the interaction of all three amino groups of the polyamine with the DNA phosphate groups on the minor groove side of the double helix. The changes in dihedral angles of the bent spermidine(3+) molecule can be explained in terms of conformational transformations of six- and seven-membered rings, analogous to cyclohexane and cycloheptane. The analysis of the position of spermidine(3+) molecule along the DNA surface reveals a sequence specificity of this binding mode with a marked preference for the narrow minor groove of A-tracts. The formation of the anomalous bent conformations of spermidine(3+) in the complex with the DNA double helix is expected to be of paramount importance in understanding the mechanisms underlying DNA's biological function