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Solvation of pharmaceutical drugs has an important effect on their structure and function. Analysis of infrared photodissociation spectra of amantadineH + (H 2 O) n =1-4 clusters in the sensitive OH, NH, and CH stretch range by quantum chemical calculations (B3LYP-D3/cc-pVTZ) provides a first impression of the interaction of this pharmaceutically active cation with water at the molecular level. The size-dependent frequency shifts reveal detailed information about the acidity of the protons of the NH 3 + group of N-protonated amantadineH + (AmaH + ) and the strength of the NH⋯O and OH⋯O hydrogen bonds (H-bonds) of the hydration network. The preferred cluster growth begins with sequential hydration of the NH 3 + group by NH⋯O ionic H-bonds ( n = 1-3), followed by the extension of the solvent network through OH⋯O H-bonds. However, smaller populations of cluster isomers with an H-bonded solvent network and free N-H bonds are already observed for n ≥ 2, indicating the subtle competition between noncooperative ion hydration and cooperative H-bonding. Interestingly, cyclic water ring structures are identified for n ≥ 3, each with two NH⋯O and two OH⋯O H-bonds. Despite the increasing destabilization of the N-H proton donor bonds upon gradual hydration, no proton transfer to the (H 2 O) n solvent cluster is observed up to n = 4. In addition to ammonium cluster ions, a small population of microhydrated iminium isomers is also detected, which is substantially lower for the hydrophilic H 2 O than for the hydrophobic Ar environment.

Oxidation of the nucleobases is of great concern for the stability of DNA strands and is considered as a source of mutagenesis and cancer. However, precise spectroscopy data, in particular in their electronic excited states are scarce if not missing. We here report an original way to produce isomer-selected radical cations of DNA bases, exemplified in the case of cytosine, through the photodissociation of cold cytosine-silver (C-Ag + ) complex. IR-UV dip spectroscopy of C-Ag + features fingerprint bands for the two keto-amino cytosine tautomers. UV photodissociation (UVPD) of the isomer-selected C-Ag + complexes produces the cytosine radical cation (C˙ + ) without isomerization. IR-UV cryogenic ion spectroscopy of C˙ + allows for the unambiguous structural assignment of the two keto-amino isomers of C˙ + . UVPD spectroscopy of the isomer-selected C˙ + species is recorded at a unique spectral resolution. These benchmark spectroscopic data of the electronic excited states of C˙ + are used to assess the quantum chemistry calculations performed at the TD-DFT, CASSCF/CASPT2 and CASSCF/MRCI-F12 levels.

In the field of nuclear energy, there is particular interest for the trapping of harmful iodine species (I 2 and CH 3 I) that could be released during a nuclear accident, due to their dangereous impact on the human metabolic processes and the environment. Here, the adsorption of these iodine molecules versus several inhibitory compounds (CO, H 2 O, CH 3 Cl and Cl 2 ) in the silver exchanged chabazite zeolite is studied in detail using ab initio molecular dynamics simulations at a realistic temperature and composition. Interestingly, we found that the iodine molecules remain attached to the cations even when the number of water molecules inside the structure is greater than two times the number of cations per cell at T = 413 K. For CO, we found that CH 3 I is more perturbed than I 2 by the presence of this inhibitor. Overall, our results indicate that the silver-exchanged chabazite zeolite is a promising candidate to trap iodine species in the case of a severe nuclear accident.

Multivalent (specifically trivalent) metal ions are known to induce microscopic phase separation (commonly termed as liquid-liquid phase separation (LLPS)) in negatively charged globular proteins even at ambient temperatures, the process being mostly driven by protein charge neutralization followed by aggregation. Recent simulation studies have revealed that such self-aggregation of proteins is entropy driven; however, it is associated with a solvation effect, which could as well be different from the usual notion of hydrophobic hydration. In this contribution we have experimentally probed the explicit change in hydration associated with ion-induced LLPS formation of a globular protein bovine serum albumin (BSA) at ambient temperature using FIR-THz FTIR spectroscopy (50-750 cm -1 ; 1.5-22.5 THz). We have used ions of different charges: Na + , K + , Ca 2+ , Mg 2+ , La 3+ , Y 3+ , Ho 3+ and Al 3+ . We found that all the trivalent ions induce LLPS; the formation of large aggregates has been evidenced from dynamic light scattering (DLS) measurements, but without perturbing the protein structure as confirmed from circular dichroism (CD) measurements. From the frequency dependent absorption coefficient ( α ( ν )) measurements in the THz frequency domain we estimate the various stretching/vibrational modes of water and we found that ions, forming LLPS, produce definite perturbation in the overall hydration, the extent of which is ion specific, invoking the definite role of hydrophilic (electrostatic) hydration of ions in the observed LLPS process.

The gas-phase structures of cationized glycine (Gly), including complexes with Li + , Na + , K + , Rb + , and Cs + , are examined using infrared multiple-photon dissociation (IRMPD) spectroscopy utilizing light generated by a free electron laser, in conjunction with ab initio calculations. To identify the structures present in the experimental studies, measured IRMPD spectra are compared to spectra calculated at B3LYP/6-311+G(d,p) for the Li + , Na + , and K + complexes and at B3LYP/def2TZVP for the Rb + and Cs + complexes. Single-point energy calculations were carried out at the B3LYP, B3P86, and MP2(full) levels using the 6-311+G(2d,2p) basis set for Li + , Na + , K + and the def2TZVPP basis set for Rb + and Cs + . The Li + and Na + complexes are identified as metal cation coordination to the amino nitrogen and carbonyl oxygen, [N,CO]-tt, although Na + (Gly) may have contributions from additional structures. The heavier metal cations coordinate to either the carbonyl oxygen, [CO]-cc, or the carbonyl oxygen and hydroxy oxygen, [CO,OH]-cc, with the former apparently preferred for Rb + and Cs + and the latter for K + . These two structures reside in a double-well potential and different levels of theory predict very different relative stabilities. Some experimental evidence is provided that MP2(full) theory provides the most accurate relative energies.

Almost all studies of specific ion binding by carboxylates (-COO - ) have considered only a single cation, but clustering of ions and ligands is a common phenomenon. We apply density functional theory to investigate how variations in the number of acetate ligands in binding to two monovalent cations affects ion binding preferences. We study a series of monovalent (Li + , Na + , K + , Cs + ) ions relevant to experimental work on many topics, including ion channels, battery storage, water purification and solar cells. We find that the preferred optimal structure has 3 acetates except for Cs + , which has 2 acetates. The optimal coordination of the cation by the carboxylate O atoms is 4 for both Na + and K + , and 3 for Li + and Cs + . There is a 4-fold coordination minimum just a few kcal mol -1 higher than the optimal 3-fold structure for Li + . For two cations, multiple minima occur in the vicinity of the lowest free energy state. We find that, for Li, Na and K, the preferred optimal structure with two cations is favored over a mixture of single cation complexes, providing a basis for understanding ionic cluster formation that is relevant for engineering proteins and other materials for rapid, selective ion transport.

Molecular dynamics simulations were performed to describe the properties of hypothetical salt electrolytic solutions. The main focus of this work is the valence asymmetry, which in recent years has been considered an important aspect in the physical chemistry of aqueous electrolytes. In general, our results show that the structural, energetic, and dynamic properties respond differently to the asymmetry of ionic solutions, but in all cases, appreciable changes were observed. Graphene supercapacitors based on the investigated electrolytes were studied in light of their electrostatic properties. We observed that the electrode capacitances, positive and negative, were greatly influenced by the presence of cations in the electrical double layer of the negative electrode and by the absence of these cations, in the double layer of the positive electrode. In general, we assess that quantitative variations due to valence asymmetry may indeed be an important factor for the development of new and more efficient electrolytes.

Supramolecular cavities have been traditionally used to stabilize reactive redox intermediates. Recently with the success of multiple new photoredox catalytic strategies that use supramolecular cages, there is a growing demand for photogeneration strategies of diverse reactive intermediates inside confined spaces, which will drive enzyme-like catalysis in real time. Here we report the excited state dynamics of a redox-active TTF radical cation and its corresponding dimethyl-derivative DiMeTTF inside a confined supramolecular cavity. We prepare the radical cation by spontaneous oxidation of neutral TTF upon incarceration inside a water-soluble nanocage Pd 6 L 4 12+ , and characterize it with a combination of resonance Raman and electron paramagnetic resonance spectroscopy. Using broadband transient absorption spectroscopy, we demonstrate that the confined native TTF radical cation and its dimethyl derivative upon photoexcitation rapidly de-excite to form the hot ground state, thereby inhibiting further oxidation to a TTF +2 dication. We discuss our results in the context of excited state crossings of the radical cation potentials as well as modifying the cage energetics to generate a stable dication. Our work has important implications for the usage of such radical cations for photoactivated catalysis.

Solvate ionic liquids (ILs) are promising candidates for several applications due to their stability, high coulombic efficiency, and low volatility. In this work, we investigate the solvation of lithium-bistriflimide by different glycerol-derived triether solvents, using molecular dynamics simulations. Very strong interactions between Li + and the solvent oxygen sites are found, leading to significant conformational changes in the solvent. By comparing the conformation of the neat solvents with their IL mixtures at different concentrations and temperatures, we find that the presence of Li + induces a distinct crown-like structure in the solvent molecules. The Li + cations and the surrounding solvent form a podand complex, which is stable even at elevated temperatures. These glycerol-derived solvents exhibit distinct interactions with Li + cations which may be exploited in electrolytic applications or lithium recovery processes.

It has been shown previously in protonated, deprotonated and ionized guanine-cytosine base pairs that intra-base pair proton transfer from the N1-H at the Watson-Crick edge of guanine to the complementary nucleobase prompts non-statistical dissociation of the base-pair system, and the dissociation of a proton-transferred base-pair structure is kinetically more favored than that of the starting, conventional base-pair structure. However, the fundamental chemistry underlying this anomalous and intriguing kinetics has not been completely revealed, which warrants the examination of more base-pair systems in different structural contexts in order to derive a generalized base-pair structure-kinetics correlation. The purpose of the present work is to expand the investigation to the non-canonical homodimeric and heterodimeric radical cations of 9-methylguanine (9MG) and 9-methyl-8-oxoguanine (9MOG), i.e. , [9MG·9MG]˙ + , [9MOG·9MG]˙ + and [9MOG·9MOG]˙ + . Experimentally, collision-induced dissociation tandem mass spectrometry coupled with an electrospray ionization (ESI) source was used for the formation of base-pair radical cations, followed by detection of dissociation product ions and cross sections in the collisions with Xe gas under single ion-molecule collision conditions and as a function of the center-of-mass collision energy. Computationally, density functional theory and coupled cluster theory were used to calculate and identify probable base-pair structures and intra-base pair proton transfer and hydrogen transfer reactions, followed by kinetics modeling to explore the properties of dissociation transition states and kinetic factors. The significance of this work is twofold: it provides insight into base-pair opening kinetics in three biologically-important, non-canonical systems upon oxidative and ionization damage; and it links non-statistical dissociation to intra-base pair proton-transfer originating from the N1-H at the Watson-Crick edge of 8-oxoguanine, enhancing understanding towards the base-pair fragmentation assisted by proton transfer.

The biological activity of the macrocycle nonactin is intimately related to its ionophore properties and ability to act as a selective cation carrier. While the focus of most investigations on nonactin has been on the binding of metal cations and small molecular ions, this study pursues the characterization of its inclusion complexes with primary amines with bulky structured side groups of different polarity. To this end, the complexes of nonactin with aniline and with the amino acid L-serine, both in protonated form, are considered as case studies and their relevant coordination arrangements are assessed by means of infrared action spectroscopy, quantum chemical density functional theory and Born-Oppenheimer molecular dynamics. The study suggests that the oxygen atoms from the oxolane (tetrahydrofuran) groups of nonactin constitute the preferential docking sites of the ammonium moiety of the guest cation, although conformational constraints promote interactions with the ester carbonyl backbone groups. In the aniline complex, the benzyl side ring is oriented outwards from the cavity, whereas in the case of L-serine, the side carboxylic acid and alcohol groups participate actively in the coordination process. Interestingly, the accommodation of L-serine is favoured when nonactin adopts an enantiomeric-selective folding, that promotes the tripodal coordination of the protonated amine group with oxolane rings from three nonactinic acid blocks with enantiomeric sequence (+)-(-)-(+), which allows for a facile coordination of the serine side groups. This is recognized as a general feature associated with the alternation of chiral domains in globally achiral natural nonactin, yielding mirror-symmetric complexes with the enantiomers of chiral amines.

We present experimental evidence for soft X-ray induced intramolecular hydrogen transfer in the protonated synthetic tri-oligonucleotide d ( F UAG) in the gas-phase ( F U: fluorouracil). The trinucleotide cations were stored in a cryogenic ion trap and exposed to monochromatic synchrotron radiation. Photoionization and photofragmentation product ion yields were recorded as a function of photon energy. Predominanly glycosidic bond cleavage leading to formation of nucleobase-related fragments is observed. In most cases, glycosidic bond cleavage is accompanied by single or double hydrogen transfer. The combination of absorption-site-sensitive soft X-ray spectroscopy with fragment specific mass spectrometry allows to directly relate X-ray absorption site and fragmentation site. We observe pronounced resonant features in the competition between single and double hydrogen transfer towards nucleobases. A direct comparison of experimental data with time-dependent density functional theory calculations, using short range corrected hybrid functionals, reveal that these hydrogen transfer processes are universal and not limited to population of particular excited states localized at the nucleobases. Instead, hydrogen transfer can occur upon X-ray absorption in any nucleobase and in the DNA backbone. Resonances seem to occur because of site-selective suppression of hydrogen transfer channels. Furthermore, non-covalent interactions of the optimized ground state geometries were investigated to identify intramolecular hydrogen bonds along which hydrogen transfer is most likely.

The photochemistry of fluorenols has been of special interest for many years. This is because both the fluorenol and the fluorenyl cation are antiaromatic in the ground state due to their 4n π-electrons according to the Hückel rule. The photolysis reaction of various fluorene derivatives takes place via a cation intermediate and is preferred due to its excited state aromaticity. Here we present an extremely long-lived fluorenyl cation and its effects on the uncaging of various leaving groups. We analyze the relationship between uncaging quantum yields of fluorene-based cages and the longevity of their fluorenyl cations with different spectroscopic methods in the steady state and on an ultrafast time scale and find that the uncaging quantum yield rises with the stability of the cation. In contrast to previous reports, the cation can be observed on a time scale of minutes, even in moderately protic solvents as methanol and ethanol. The stability of this cation depends on the dimethylamino-substituents on the fluorene scaffold and the properties of the solvent. In addition, with bis-dimethylamino fluorenol, a photobase is introduced that expands the small group of known photoinduced hydroxide emitters.

In contrast to their spontaneous deprotonation in aqueous solution, reactions of guanine and guanosine radical cations with water in the gas phase are exclusively initiated by hydration of the radical cations as reported in recent work (Y. Sun et al. , Phys. Chem. Chem. Phys. , 2018, 20 , 27510). As gas-phase hydration reactions closely mimic the actual scenario for guanine radical cations in double-stranded DNA, exploration of subsequent reactions within their water complexes can provide an insight into the resulting oxidative damage to nucleosides. Herein guided-ion beam mass spectrometry experiment and direct dynamics trajectory simulations were carried out to examine prototype complexes of the 9-methylguanine radical cation with one and two water ligands ( i.e. , 9MG˙ + ·(H 2 O) 1-2 ) in the gas phase, wherein the complexes were activated by collisional activation in the experiment and by thermal excitation at high temperatures in the simulations. Guided by mass spectroscopic measurements, trajectory results and reaction potential energy surface, three reaction pathways were identified. The first two reaction pathways start with H-atom abstraction from water by the O6 and N7 atoms in 9MG˙ + and are referred to as HA O6 and HA N7 , respectively. The primary products of HA O6 and HA N7 reactions, including [9MG + H O6 ] + /[9MG + H N7 ] + and ˙OH, react further to either form [8OH-9MG + H O6 ]˙ + and [8OH-9MG + H N7 ]˙ + via C8-hydroxylation or form radical cations of 6- enol -guanine (6- enol -G˙ + ) and 7H-guanine (7HG˙ + ) via S N 2-type methanol elimination. The third reaction pathway corresponds to the formation of 8OH-9MG + by H elimination from the complex, referred to as HE. Among these product channels, [8OH-9MG + H N7 ]˙ + has the most favorable formation probability, especially in the presence of additional water molecules. This product may serve as a preceding structure to the 8-oxo-7,8-dihydroguanine lesion in DNA and has implications for health effects of radiation exposure and radiation therapy.

G-Quadruplex (Gq) formation and stabilization by any molecule is an essential requirement for its application in therapy, especially in oncology. Metal cations have shown higher propensity of the formation of the Gq structure and its stabilization. In this study, the role of both cations and anions of ionic liquids (ILs) on the Gq formation of human telomere (hTeloG) and its stability was investigated using spectroscopic and molecular dynamics simulation techniques. Irrespective of the nature of anions of ILs, tetramethylguanidinium (TMG) cations associated with different anions can form an antiparallel Gq structure in hTeloG. However, the propensity of the formation of an antiparallel Gq structure and its stability depend on the chain length of anions of ILs. Gq is significantly less stable in ILs having longer hydrocarbon chain anions compared to the short chain anions suggesting that the hydrophobicity of the anion plays a critical role in the stability and formation of the Gq structure by ILs. The data indicate that longer hydrocarbon chain anions of ILs preferably interact in the loop region of Gq through hydrophobic interaction which enhances the overall binding of the cation of ILs with Gq causing a decrease in the stacking energy between the G-quartets as well as Hoogsteen hydrogen bonds between the guanine bases leading to the destabilization of the antiparallel Gq structure.

Electrostatic interactions are central to the structure and function of nucleic acids, including their folding, condensation, and interaction with proteins and other charged molecules. These interactions are profoundly affected by ions surrounding nucleic acids, the constituents of the so-called ion atmosphere. Here, we report precise Fourier Transform-Terahertz/Far-Infrared (FT-THz/FIR) measurements in the frequency range 30-500 cm -1 for a 24-bp DNA solvated in a series of alkali halide (NaCl, NaF, KCl, CsCl, and CsF) electrolyte solutions which are sensitive to changes in the ion atmosphere. Cation excess in the ion atmosphere is detected experimentally by observation of cation modes of Na + , K + , and Cs + in the frequency range between 70-90 cm -1 . Based on MD simulations, we propose that the magnitude of cation excess (which is salt specific) depends on the ability of the electrolyte to perturb the water network at the DNA interface: In the NaF atmosphere, the ions reduce the strength of interactions between water and the DNA more than in case of a NaCl electrolyte. Here, we explicitly take into account the solvent contribution to the chemical potential in the ion atmosphere: A decrease in the number of bound water molecules in the hydration layer of DNA is correlated with enhanced density fluctuations, which decrease the free energy cost of ion-hydration, thus promoting further ion accumulation within the DNA atmosphere. We propose that taking into account the local solvation is crucial for understanding the ion atmosphere.

G protein-gated inwardly rectifying potassium (GIRK) channels play essential roles in electrical signaling in neurons and muscle cells. Nonequilibrium environments provide crucial driving forces behind many cellular events. Here, we apply the antiparallel alignment double bilayer model to study GIRK2 in response to the time-dependent membrane potential. Using molecular dynamics and umbrella sampling, we examined the time-dependent environmental impact on the ion conduction, energy basis, and primary motions of GIRK2 in different complex states with phosphatidylinositol-4,5-bisphosphate (PIP2) and G-protein βγ subunits (Gβγ). The antiparallel alignment double bilayer model enables us to study the transport performance in inward and outward K+ and mixed K+ and Na+. We obtained the recoverable discharge process of GIRK2 complexed with both PIP2 and Gβγ, compared with occasional conduction under PIP2-only regulation. Calculations of potential of mean force suggest different regulation by the helix bundle crossing (HBC) gate and G-loop gate regarding different complex states and under a membrane potential. In a nonequilibrium environment, distinct functional rocking motions of GIRK2 were identified under strengthened correlations between the transmembrane helices and downstream cytoplasmic domains with binding of PIP2, cations, and Gβγ. The findings suggest the potential domain motions and dynamics associated with a nonequilibrium environment and highlight the application of the antiparallel alignment double bilayer model to investigate factors in an asymmetric environment.

Cations play a critical role in the stability and morphology of lipid-A aggregates by neutralizing, hydrating and cross-linking these glycolipid molecules. Monophosphorylated lipid-A is the major immunostimulatory principle in commercially available adjuvants containing Al3+ such as adjuvant system 04 (AS04). The antagonist/agonist immunomodulatory properties of lipid-A are associated with chemical variations (e.g. the number of acyl chains and phosphate groups) and their aggregate arrangements (e.g. lamellar, nonlamellar or mixed). Therefore, the identification of the active form of lipid-A can provide valuable guidance in the development of vaccine adjuvants capable of boosting the immune system with decreased reactogenicity. Although the effect of mono and divalent cations on the structural polymorphism and endotoxicity of LPS has been previously investigated, much less is known about the effect of trivalent cations. We have investigated the effect of NaCl and AlCl3 salt solutions on the structural dynamics and stability of mono and diphosphorylated lipid-A membranes via atomistic MD simulations. The Al3+ ion exerts two major effects on the structural dynamics of lipid-A membranes. It acts as an efficient cross-linker of mono or diphosphorylated lipid-A molecules, thus stabilizing the lamellar arrangement of these glycolipids. It also alters the lipid-A packing and membrane fluidity, inducing disorder → order structural transitions of the membrane. This effect is promptly reversed upon the addition of NaCl solution, which promotes a nearly threefold increase in the amount of water in the carbohydrate moiety of the Al3+-containing lipid-A membranes. The exchange dynamics and residence times of cation-coordinated water molecules in these membranes provide insights into the molecular mechanism for the Na+-induced transition from a densely packed ordered phase to a disordered one. Al3+ counter-ions favor ordered lamellar aggregates, which has been previously associated with the lack of endotoxic activity and cytokine-inducing action. The resulting microscopic understanding of the structure and dynamics of lipid-A aggregates in the presence of Al3+ and Na+ salts can provide valuable guidance in the development of vaccine adjuvants capable of boosting the immune system with decreased reactogenicity.

Adsorption processes are central to ionic transport in industrial and biological membrane systems. Multivalent cations modulate the conductive properties of nanofluidic devices through interactions with charged surfaces that depend principally on the ion charge number. Considering that ion channels are specialized valves that demand a sharp specificity in ion discrimination, we investigate the adsorption dynamics of trace amounts of different salts of trivalent cations in biological nanopores. We consider here OmpF from Escherichia coli, an archetypical protein nanopore, to probe the specificity of biological nanopores to multivalent cations. We systematically compare the effect of three trivalent electrolytes on OmpF current-voltage relationships and characterize the degree of rectification induced by each ion. We also analyze the open channel current noise to determine the existence of equilibrium/non-equilibrium mechanisms of ion adsorption and evaluate the extent of charge inversion through selectivity measurements. We show that the interaction of trivalent electrolytes with biological nanopores occurs via ion-specific adsorption yielding differential modulation of ion conduction and selectivity inversion. We also demonstrate the existence of non-equilibrium fluctuations likely related to ion-dependent trapping-detrapping processes. Our study provides fundamental information relevant to different biological and electrochemical systems where transport phenomena involve ion adsorption in charged surfaces under nanoscale confinement.

The "specific" interaction between metal cations (Na + , Ca 2+ , Mg 2+ , and Zn 2+ ) and the charged COO - group, and the "non-specific" interaction between these cations and the peptide backbone of a zwitterionic trialanine (Ala3) in aqueous solutions were examined in detail, using linear infrared (IR) absorptions of the COO - symmetric stretching and the amide-II (mainly the C-N stretching) modes as IR probes. Different IR spectral changes in peak positions and intensities of the two IR probes clearly demonstrate their sensitivities to nearby cation distributions in distance and population. Quantum chemistry calculations and molecular dynamics simulations were used to describe the cation-peptide interaction picture. These combined results suggest that Na + and Ca 2+ tend to bind to the COO - group in the bidentate form, while Mg 2+ and Zn 2+ tend to bind to the COO - group in the pseudo-bridging form. The results also show that while all three divalent cations indirectly interact with the peptide backbone with large population, Ca 2+ and Mg 2+ can be sometimes distributed very close to the backbone. Such a non-specific cation interaction can be moderately sensed by the C-N stretching of the amide-II mode when cations approach the polar amide C[double bond, length as m-dash]O group, and is also influenced by the NH 3 + charge group located at the N-terminus. The results suggest that the experimentally observed complication of the Hofmeister cation series shall be understood as a combined specific and non-specific cation-peptide interactions.

A guided-ion beam tandem mass spectrometric study was performed on collision-induced dissociation (CID) of a protonated 9-methylguanine-1-methylcytosine Watson-Crick base pair (designated as WC-[9MG·1MC + H] + ), from which dissociation pathways and dissociation energies were determined. Electronic structure calculations at the DFT, RI-MP2 and DLPNO-CCSD(T) levels of theory were used to identify product structures and delineate reaction mechanisms. Intra-base-pair proton transfer (PT) of WC-[9MG·1MC + H] + results in conventional base-pair conformations that consist of hydrogen-bonded [9MG + H] + and 1MC and proton-transferred conformations that are formed by PT from the N1 of [9MG + H] + to the N3' of 1MC. Two types of conformers were distinguished by CID in which the conventional conformers produced [9MG + H] + product ions whereas the proton-transferred conformers produced [1MC + H] + . The conventional conformers have a higher population (99.8%) and lower dissociation energy than the proton-transferred counterparts. However, in contrast to what was expected from the statistical dissociation of the equilibrium base-pair conformational ensemble, the CID product ions of WC-[9MG·1MC + H] + were dominated by [1MC + H] + rather than [9MG + H] + . This finding, alongside the non-statistical CID reported for deprotonated guanine-cytosine (Lu et al.; PCCP, 2016, 18, 32222) and guanine-cytosine radical cation (Sun et al.; PCCP, 2020, 22, 14875), reinforces that non-statistical dissociation is a distinctive feature of singly-charged Watson-Crick guanine-cytosine base pairs. It implies that intra-base-pair PT facilitates the formation of proton-transferred conformers in these systems and the ensuing conformers have loose transition states for dissociation. The monohydrate of WC-[9MG·1MC + H] + preserves non-statistical CID kinetics and introduces collision-induced methanol elimination via the reaction of the water ligand with a methyl group.

Hydrogen-rich cation radicals (GATT + 2H) + ˙ and (AGTT + 2H) + ˙ represent oligonucleotide models of charged hydrogen atom adducts to DNA. These tetranucleotide cation radicals were generated in the gas phase by one-electron reduction of the respective (GATT + 2H) 2+ and (AGTT + 2H) 2+ dications in which the charging protons were placed on the guanine and adenine nucleobases. We used wavelength-dependent UV/Vis photodissociation in the valence-electron excitation region of 210-700 nm to produce action spectra of (GATT + 2H) + ˙ and (AGTT + 2H) + ˙ that showed radical-associated absorption bands in the near-UV (330 nm) and visible (400-440 nm) regions. Born-Oppenheimer molecular dynamics and density-functional theory calculations were used to obtain and rank by energy multiple (GATT + 2H) dication and cation-radical structures. Time-dependent density functional theory (TD-DFT) calculations of excited-state energies and electronic transitions in (GATT + 2H) + ˙ were augmented by vibronic spectra calculations at 310 K for selected low-energy cation radicals to provide a match with the action spectrum. The stable product of one-electron reduction was identified as having a 7,8-dihydroguanine cation radical moiety, formed by intramolecular hydrogen atom migration from adenine N-1-H. The hydrogen migration was calculated to have a transition state with a low activation energy, E a = 96.5 kJ mol -1 , and positive activation entropy, ΔS ‡ = 75 J mol -1 K -1 . This allowed for a fast isomerization of the primary reduction products on the ion-trap time scale of 150 ms that was substantially accelerated by highly exothermic electron transfer.

Deep sea biology is known to thrive at pressures up to ≈1 kbar, which motivates fundamental biophysical studies of biomolecules under such extreme environments. In this work, the conformational equilibrium of the lysine riboswitch has been systematically investigated by single molecule FRET (smFRET) microscopy at pressures up to 1500 bar. The lysine riboswitch preferentially unfolds with increasing pressure, which signals an increase in free volume (ΔV0 > 0) upon folding of the biopolymer. Indeed, the effective lysine binding constant increases quasi-exponentially with pressure rise, which implies a significant weakening of the riboswitch-ligand interaction in a high-pressure environment. The effects of monovalent/divalent cations and osmolytes on folding are also explored to acquire additional insights into cellular mechanisms for adapting to high pressures. For example, we find that although Mg2+ greatly stabilizes folding of the lysine riboswitch (ΔΔG0 < 0), there is negligible impact on changes in free volume (ΔΔV0 ≈ 0) and thus any pressure induced denaturation effects. Conversely, osmolytes (commonly at high concentrations in deep sea marine species) such as the trimethylamine N-oxide (TMAO) significantly reduce free volumes (ΔΔV0 < 0) and thereby diminish pressure-induced denaturation. We speculate that, besides stabilizing RNA structure, enhanced levels of TMAO in cells might increase the dynamic range for competent riboswitch folding by suppressing the pressure-induced denaturation response. This in turn could offer biological advantage for vertical migration of deep-sea species, with impacts on food searching in a resource limited environment.

Metalloproteins are crucial to many biological processes, such as photosynthesis, respiration, and efficient electron transport. Zinc is the most common transition metal found in proteins and is critical for structure, function and stability, however the effects from the electronic properties of a bound zinc ion on electron transfer are not clearly defined. Here, a series of β-strand and 310-helical peptides, capable of binding Zn2+via suitably positioned His residues, was synthesized and their ability to undergo electron transfer in the presence and absence of Zn2+ studied by electrochemical and computational means. The β-strand peptide was shown to be conformationally pre-organized, with this geometry maintained on complexation with zinc. Electrochemical studies show a significant increase in charge transport, following binding of the zinc ion to the β-strand peptide. In contrast, complexation of zinc to the helical peptide disrupts the intramolecular hydrogen bonding network known to facilitate electron transfer and leads to a loss of secondary structure, resulting in a decrease in charge transfer. These experimental and computational studies reveal an interplay, which demonstrates that bound zinc enhances charge transfer by changing the electronic properties of the peptide, and not simply by influencing secondary structure.

There is emerging interest in the role of lanthanides as cofactors for XoxF-type methanol dehydrogenase (MDH). Here, classical molecular dynamics simulations combined with fragment molecular orbital calculations were employed to rationalize the enzymatic activities of MDH (both XoxF- and MxaF-types) carrying different lanthanides. In XoxF-type MDH, lanthanide binding to cofactor pyrroloquinoline quinone was found to switch from tridentate to unidentate fashion as it switches from lighter to heavier lanthanides. This fact possibly plays a crucial role in the enzymatic activity exclusive to XoxF-type MDH incorporating lighter lanthanides.

The first step in the biodegradation of imidazolium-based ionic liquids involves the insertion of the -OH group into the alkyl side chain, and it is believed to be triggered by cytochrome P450. However, at present, there is a lack of fundamental understanding of why the hydroxylation process is observed only for longer alkyl chain analogues. As the initial step of the hydroxylation reaction involves the ionic liquid binding to Fe-porphyrin (FeP) - the catalytic center of cytochrome P450, the orientation of ionic liquids presented to FeP is expected to play a crucial role in eventual hydroxylation of the alkyl side chain. In order to elucidate the chain-length dependent binding preferences exhibited by the homologous series of 1-n-alkyl-3-methylimidazolium (n = 2, 4, 6, 8, and 10) [Cnmim]+ cations, a quantum mechanical treatment of the cations in the presence of free base porphyrin (FBP) and FeP is carried out at the B3LYP-D2 and M06 levels. The binding energy of different complexes with FBP and FeP is investigated by considering three vastly different starting relative orientations of the cations with respect to FBP and FeP: tail down, tail up, and interplanar. Our calculations of binding energies reveal that the cation orientations initiated from the tail down conformations (alkyl chain facing the porphyrin molecules) are progressively destabilized as the alkyl chain length increases. The decomposition of the binding energies into various energetic contributions shows that the interaction energy between the cations and porphyrin molecules varies with the cation geometries presented to porphyrin molecules and is the primary determinant of the magnitude of the binding energies. We further demonstrate that the propensity of the cation-FeP complexes to acquire an electron, the next step in the hydroxylation reaction cycle upon substrate binding, is favored independent of the cations and conformations, suggesting that this step is not the reason for the low biodegradability of short alkyl chain bearing cations. Furthermore, the weaker binding of the ionic liquid to FeP is anticipated to facilitate dioxygen binding to FeP, the step following the electron transfer reaction. Overall, the results of the present calculations indicate that the destabilization of the tail down conformations relative to the other two conformations correlates with the experimental results of the chain length-dependent biodegradation of imidazolium-based ionic liquids.

We present the first, to the best of our knowledge, ab initio molecular dynamics (AIMD) investigation on three aqueous solutions where an abasic cyclic nucleotide model is solvated in the presence of distinct cations (i.e., Na + , K + and Mg 2+ ). We elucidate the typical modalities of interaction between those ionic species and the nucleotide moiety by first-principles numerical simulations, starting from an inner-shell binding configuration on a time scale of 100 ps (total simulation time of ∼600 ps). Whereas the strong "structure-maker" Mg 2+ is permanently bound to one of the two oxygen atoms of the phosphate group of the nucleotide model, Na + and K + show binding times τ b of 65 ps and 10-15 ps, respectively, thus reflecting their chemical nature in aqueous solutions. Furthermore, we qualitatively relate these findings to approximate free-energy barriers of the cations' unbinding obtained by means of exploratory well-tempered metadynamics. With the aim of shedding light on the features of commonly employed force-fields (FFs), classical MD simulations (almost 200 trajectories with a total simulation time of ∼18 μs) using the biomolecular AMBER FF are also reported. By choosing several combinations of the parametrization for the water environment (i.e., TIP3P, SPC/E and OPC) and cations (i.e., Joung-Cheatham, Li-Merz 12-6 and Li-Merz 12-6-4), we found significant differences in the radial distribution functions and residence times compared to the ab initio results. The Na + and K + ions wrongly show quasi-identical radial distribution functions and the Li & Merz 12-6-4 Lennard-Jones parameters for Mg 2+ were found to be essential in quickly reaching the binding state consistent with AIMD.

Trivalent yttrium cations are able to mimic the behavior of Ca2+ in many important biochemical processes, and their application in medicinal chemistry has increased in recent years. While the effect of mono- and divalent salts on lipid membranes has been studied extensively, the effect of trivalent cations, such as Y3+, on the structure and phase behavior of lipid bilayers is largely unknown. Here, we studied the effect of YCl3 on the structure, phase behavior and thermodynamic parameters of zwitterionic DPPC, 20% anionic DPPC/DPPG (80/20) and 10% anionic DOPC/DOPG/DPPC/DPPG/cholesterol (20/5/45/5/25) model biomembrane systems using Fourier-transform infrared spectroscopy, differential scanning calorimetry, Laurdan fluorescence spectroscopy, confocal fluorescence microscopy, zeta potential measurements and atomic force microscopy, covering a wide range of salt concentrations, temperature and pressure. Y3+ ions penetrate deep into the lipid headgroup region and are coordinated to the phosphate groups, resulting in a stronger lipid packing and partial dehydration of the headgroup region. Increasing Y3+ concentration leads to a pronounced increase of the gel-to-fluid phase transition temperature of the phospholipid bilayers, owing to an increased lateral compression pressure, particularly for anionic lipid membranes. Increased lipid chain order and phase segregation of anionic membranes is fostered at high salt concentrations owing to lipid sorting. The fluid-to-gel phase transition pressure decreases significantly with the concentration of the trivalent ion, most pronounced for the negatively charged lipid vesicles. Remarkably, the Y3+-induced ordering effect is much stronger than a hydrostatic pressure-induced ordering of the lipid chains.

The reactions of D2O with radical cations of guanine (9HG˙+), 9-methylguanine (9MG˙+), 2'-deoxyguanosine (dGuo˙+) and guanosine (Guo˙+) were studied in the gas phase, including measurements of reaction cross sections over a center-of-mass collision energy (Ecol) range from 0.1 to 2.0 eV and computation of reaction pathways at DLPNO-CCSD(T)/aug-cc-pVTZ//ωB97XD/6-31+G(d,p). Reaction efficiencies of all radical cations are well below unity (∼2% of collision rate), despite there being exoergic pathways. For each reactant ion, the energetically most favorable product channel corresponds to the formation of water complexes; however, this channel accounts for only 5% of the total cross section at the lowest Ecol and becomes negligible at high Ecol due to short complex lifetimes. The dominant product channel is H/D exchange that appears to be complex-mediated at low Ecol, but switches to a direct mechanism and accompanies keto-enol isomerization of the guanine moiety when Ecol increases. C8-hydroxylation, a minor yet the most biologically important channel, was observed for 9HG˙+; and its mechanism was elucidated in the presence of single and double water molecules, of which the second water eliminates the barrier for C8-addition via a proton shuttle mechanism. All reactions show strong dependence on radical structures, with overall reactivity being 9HG˙+ ≫ 9MG˙+ > dGuo˙+ ≈ Guo˙+. The reaction dynamics of 9HG˙+ and 9MG˙+ with water were simulated at Ecol = 0.1 eV using ωB97XD/6-31+G(d), to reveal complex formation at the early stage of the reaction and the effects of N9-substitution. Trajectory results suggest that the lack of a W9 complex (water bonded to N9-H) is responsible for the reduced reactivity of N9-substituted radical cations; but the relatively long-lived W16 complexes (water bonded to N1-H and C6-O) of dGuo˙+ and Guo˙+ may enhance keto-enol isomerization.

In the presence of trivalent cations, negatively charged globular proteins show a rich phase behaviour including reentrant condensation, crystallisation, clustering and lower critical solution temperature metastable liquid-liquid phase separation (LCST-LLPS). Here, we present a systematic study on how different multivalent cations can be employed to tune the interactions and the associated phase behaviour of proteins. We focus our investigations on the protein bovine serum albumin (BSA) in the presence of HoCl3, LaCl3 and YCl3. Using UV-Vis spectroscopy and small-angle X-ray scattering (SAXS), we find that the interprotein attraction induced by Ho3+ is very strong, while the one induced by La3+ is comparatively weak when comparing the data to BSA-Y3+ systems based on our previous work. Using zeta potential and isothermal titration calorimetry (ITC) measurements, we establish different binding affinities of cations to BSA with Ho3+ having the highest one. We propose that a combination of different cation features such as radius, polarisability and in particular hydration effects determine the protein-protein interaction induced by these cations. Our findings imply that subtle differences in cation properties can be a sensitive tool to fine-tune protein-protein interactions and phase behaviour in solution.

Self-assembled structures formed by mixtures of cationic and anionic surfactants are interesting tools for applications requiring interactions with charged particles and molecules. Nevertheless, they present instability close to the equimolar composition and poor morphological versatility, which is generally restricted to vesicles and micelles. Against this general trend, we report on bile salt derivative based catanionic mixtures assembling in tubules and lamellae depending on the mixture composition. Electrophoretic mobility measurements prove that the composition also dictates their superficial charge, which can be tuned from negative to positive by increasing the positively charged surfactant fraction in the mixtures. The study of the catanionic aggregates was conducted by means of microscopy and spectroscopy techniques and compared to the self-assembly behaviors of the individual building blocks. This study broadens the so far small array of bile salt derivative catanionic systems, confirming their distinctive behavior in the spectrum of catanionic mixtures.

The ionic liquid (IL) 1-ethyl-3-methylimidazolium acetate ([EMIM]Acetate) has been widely used for biomass processing, i.e., to pretreat, activate, or fractionate lignocellulosic biomass to produce soluble sugars and lignin. However, this IL does not achieve high biomass solubility, therefore minimizing the efficiency of biomass processing. In this study, [EMIM]Acetate and three other ILs composed of different 3-methylimidazolium cations and carboxylate anions ([EMIM]Formate, 1-allyl-3-methylimidazolium ([AMIM]) formate, and [AMIM]Acetate) were analyzed to relate their physicochemical properties to their biomass solubility performance. While all four ILs are able to dissolve hybrid poplar under fairly mild process conditions (80 °C and 100 RPM stirring), [AMIM]Formate and [AMIM]Acetate have particularly increased biomass solubility of 40 and 32%, respectively, relative to [EMIM]Acetate. Molecular dynamics simulations suggest that strong interactions between IL and specific plant biopolymers may contribute to this enhanced solubilization, as the calculated second virial coefficients between ILs and hemicellullose are most favorable for [AMIM]Formate, matching the trend of the experimental solubility measurements. The simulations also reveal that the interactions between the ILs and hemicellulose are an important factor in determining the overall biomass solubility, whereas lignin-IL interactions were not found to vary significantly, consistent with literature. The combined experimental and simulation studies identify [AMIM]Formate as an efficient biomass solvent and explain its efficacy, suggesting a new approach to rationally select ionic liquid solvents for lignocellulosic deconstruction.

Cationic lipids are considered as non-viral carriers for genetic material used in gene therapy. They have no carcinogenic potential and cause low immune response compared to existing viral systems. The protonation degree of these cationic lipids is a crucial parameter for the binding behavior of polynucleotides (e.g., DNA). Newly synthesized peptide-mimic lysine-based amino-functionalized lipids have been investigated in 2D models as monolayers at the air-liquid interface. Standard surface pressure - area isotherms have been measured to prove the layer stability. Total reflection X-ray fluorescence (TRXF) has been used as a surface sensitive analytical method to estimate the amount of counterions at the head groups. Using a standard sample as a reference, the protonation degree of these cationic lipids can be quantified on buffers with different pH values. It is found that the protonation degree depends linearly on the packing density of the lipid monolayer.

The interactions of bovine serum albumin (BSA) with aggregates of cationic polymers, i.e. quaternized poly(chloromethyl styrene) chains (QIm-PCMS), in aqueous solutions are investigated using small angle neutron scattering on length scales relevant to the size of BSA. The arrangement of the macromolecular chains within their aggregates is consistent with a blob description of overlapping chains that contain hydrophobic domains. The local conformations depend on the salt content as in typical linear polyelectrolytes. Although the hydrophobic content of the cationic polymers does not cause measurable local morphology differences, the interactions with BSA are enhanced in the case of the not fully quaternized polymer. The secondary structure of BSA is critically compromised by the interaction with the quaternized polymers as the signature of the alpha helix conformation is lost. The complexation with BSA and the resulting enhancement of interchain associations on higher length scales are verified using dynamic light scattering experiments. This study demonstrates the ability to tune the polyelectrolyte/protein interactions and polyelectrolyte chain-chain associations by modifying the hydrophobic content of the polyelectrolytes.

The antibiotic activity of nonactin is sustained by its ability to transport K + across lipophilic phases, e.g., the cell membranes. Such a feature can be traced back to a specific ionophoric behavior and to a balanced hydrophobicity modulated by the formation of a cation complex. In this study, the dominant conformations and coordination arrangements in the alkali cation complexes (Na + , K + , Cs + ) of nonactin are characterized by means of action vibrational spectroscopy and quantum chemical computations. The low energy conformers of the complexes comprise compact inclusion structures, in which the cation interacts with a varying number of oxygen atoms of the carbonyl and oxolane ring groups of the nonactin macrocycle. The spectroscopy experiments indicate that the three alkali complexes explored are formed in a S 4 conformation. This is in contrast with previous crystallography studies, which concluded that the symmetry of the most stable conformer of the complex changes qualitatively with the cation size, from C 2 for Na + to S 4 for K + and Cs + . Computations with different hybrid density functionals lead to contradictory predictions that appear to be quite sensitive to the modelling of the long range interactions in the coordination arrangements. The stabilization of the nonactin-Na + complex in the C 2 or S 4 forms emerges as a subtle feature that may be tuned with an appropriate control of the environmental conditions, and constitutes a challenging benchmark to confront novel computational methods for supramolecular systems.

Fluorescent 3H-indolium cations are valuable components for the realization of activatable fluorophores for bioimaging applications. Their relatively poor fluorescent quantum yields in organic solvents, however, appear to be in contradiction to their good performance in analytical methods based on single-molecule detection. The elucidation of the structural factors governing the excitation dynamics of these compounds is, therefore, essential to rationalize these effects and possibly guide the future design of activatable probes with improved performance. In this context, the structural, photochemical and photophysical properties of a model compound, consisting of coumarin and 3H-indolium heterocycles separated by a [C-C[double bond, length as m-dash]C-C] bridge, were characterized with a combination of experimental and theoretical analyses. These studies demonstrate that the fast rotation about the [C-C] bond adjacent to the coumarin component competes with the radiative deactivation of the excited state in nonviscous environments. This geometrical change dislodges the coumarin and 3H-indolium cations out of planarity to allow the population of a weakly-emissive twisted intramolecular charge-transfer (TICT) state and produce fluorescence with low quantum yield. In viscous environments, the conformational change is slow and cannot compete effectively with the radiative deactivation of the excited state, which instead produces fluorescence with high quantum yield. These results indicate that structural modifications aimed at the restriction of the rotation of this [C-C] bond are essential to improve considerably the fluorescence quantum yield of this chromophoric platform. Should a synthetic strategy for the implementation of these design guidelines be identified, activatable fluorophores, based on the 3H-indolium platform, with improved brightness will ultimately emerge.

We have applied the umbrella sampling (US) method in all-atom molecular dynamics (MD) simulations to obtain potential of mean force (PMF) profiles for ion transport through three representative G-quadruplex DNA channels: [d(TG 4 T)] 4 , [d(G 3 T 4 G 4 )] 2 , and d[G 4 (T 4 G 4 ) 3 ]. The US MD results are in excellent agreement with those obtained previously with the adaptive biasing force (ABF) method. We then utilized the unique features in the US MD method to investigate multi-ion effects in [d(G 3 T 4 G 4 )] 2 and discovered that the concerted ion movement is crucial for fully explaining the unusual experimental results on ion movement in this particular G-quadruplex system. We anticipate that these modern free-energy methods will be useful tools in evaluating ion transport properties of other G-quadruplex DNA channels.

Cation-π interactions of aromatic rings and positively charged groups are among the most important interactions in structural biology. The role and energetic characteristics of these interactions are well established. However, the occurrence of cation-π-cation interactions is an unexpected motif, which raises intriguing questions about its functional role in proteins. We present a statistical analysis of the occurrence, composition and geometrical preferences of cation-π-cation interactions identified in a set of non-redundant protein structures taken from the Protein Data Bank. Our results demonstrate that this structural motif is observed at a small, albeit non-negligible frequency in proteins, and suggest a preference to establish cation-π-cation motifs with Trp, followed by Tyr and Phe. Furthermore, we have found that cation-π-cation interactions tend to be highly conserved, which supports their structural or functional role. Finally, we have performed an energetic analysis of a representative subset of cation-π-cation complexes combining quantum-chemical and continuum solvation calculations. Our results point out that the protein environment can strongly screen the cation-cation repulsion, leading to an attractive interaction in 64% of the complexes analyzed. Together with the high degree of conservation observed, these results suggest a potential stabilizing role in the protein fold, as demonstrated recently for a miniature protein (Craven et al., J. Am. Chem. Soc. 2016, 138, 1543). From a computational point of view, the significant contribution of non-additive three-body terms challenges the suitability of standard additive force fields for describing cation-π-cation motifs in molecular simulations.

Despite the fact that fluorination makes a drug more lipophilic, the molecular level understanding of protein-fluorinated drug interactions is very poor. Due to their enhanced ability to penetrate the blood brain barrier, they are suitable for reactivation of organophosphorus inactivated acetylcholinesterase (AChE) in the central nervous system. We systematically studied the unbinding of fluorinated obidoxime (FOBI) and non-fluorinated obidoxime (OBI) from the active site gorge of the serine hydrolase AChE in mean field polarizable water by employing all atom molecular dynamics simulations. It is observed that the unbinding process is strongly influenced by cation-π, hydrogen bond (HB) and water bridge interactions. The FOBI drug interacts more strongly with the protein residues than OBI and this is also verified from quantum mechanical calculations. Distinct unbinding pathways for FOBI and OBI are observed as evident from the 1D and 2D potential of mean force of the unbinding profiles. The present study suggests that the FOBI drug is held more firmly in the gorge of AChE in comparison to OBI and may lead to higher reactivation efficiency of the inactivated enzyme.

The structures and stabilities of self-assembled guanine quadruplexes, M(9eG) 8 + (M = Na, K, Rb, Cs; 9eG = 9-ethylguanine), have been studied in the gas phase by blackbody infrared radiative dissociation to determine the difference in the stabilizing effect of the alkali metal cations. The order of stabilities to decomposition was determined to be K + > Rb + > Cs + ≫ Na + , which is consistent with the observation of K + being the ion of choice in guanine quadruplexes in nucleic acids. In the gas phase, the sodiated quadruplex was found to lose one 9eG at a time, whereas the quadruplexes of the heavier cations lost a neutral guanine tetrad. Vibrational spectroscopy on the gas-phase quadruplex ions was consistent with the structures in which the metal cations were sandwiched between two guanine tetrads. Electronic structure calculations are also used to compare with the observed stabilities and vibrational spectra.

Despite the vast amount of experimental and theoretical studies on the binding affinity of cations - especially the biologically relevant Na + and Ca 2+ - for phospholipid bilayers, there is no consensus in the literature. Here we show that by interpreting changes in the choline headgroup order parameters according to the 'molecular electrometer' concept [Seelig et al., Biochemistry, 1987, 26, 7535], one can directly compare the ion binding affinities between simulations and experiments. Our findings strongly support the view that in contrast to Ca 2+ and other multivalent ions, Na + and other monovalent ions (except Li + ) do not specifically bind to phosphatidylcholine lipid bilayers at sub-molar concentrations. However, the Na + binding affinity was overestimated by several molecular dynamics simulation models, resulting in artificially positively charged bilayers and exaggerated structural effects in the lipid headgroups. While qualitatively correct headgroup order parameter response was observed with Ca 2+ binding in all the tested models, no model had sufficient quantitative accuracy to interpret the Ca 2+ :lipid stoichiometry or the induced atomistic resolution structural changes. All scientific contributions to this open collaboration work were made publicly, using nmrlipids.blogspot.fi as the main communication platform.

DNA photosensitization is one of the physical processes behind photodynamic therapy techniques, i.e. the combined use of photoactive drugs and visible radiation for therapeutical purposes. In this contribution we report the analysis of the photophysical properties of a two-photon absorption dye together with its interaction with DNA. The linear and non-linear optical properties are modeled taking into account the complex environment including dynamic and vibrational effects. It is also clearly demonstrated that the excited state manifold may evolve toward spontaneous photoionization with the production of a solvated electron. In turn both the radical cation and the solvated electron may react with the DNA backbone to produce a strand break; hence we have characterized a phototherapeutic dye that absorbs in the infrared region and is able to work under hypoxidic conditions, i.e. a prodrug of great interest for the potential treatment of solid tumors.

A simple procedure for the preparation of giant vesicles using surface active ionic liquids (SAILs) has been provided in this paper. SAILs, used to form vesicles, were synthesized by replacing the cationic part of Aerosol OT (AOT) with cations having alkyl chains of different lengths (ammonium and imidazolium cations). The number of carbons in the alkyl chains of the cations was varied from eight to sixteen. From the observed results, the formation of giant vesicles is found to be dependent on the alkyl chain length as well as the organic moieties of the respective cations. These giant vesicles were characterized using fluorescence lifetime imaging microscopy (FLIM). The conformational dynamics of bovine serum albumin (BSA) inside these giant vesicles was determined using fluorescence correlation spectroscopy (FCS) to get an idea about the protein dynamics in a constrained environment. The interaction of the giant vesicles with the protein was confirmed by the change in the diffusion coefficient and the conformational fluctuation time.

By providing accurate distance measurements between spin labels site-specifically attached to bio-macromolecules, double electron-electron resonance (DEER) spectroscopy provides a unique tool to probe the structural and conformational changes in these molecules. Gd(3+)-tags present an important family of spin-labels for such purposes, as they feature high chemical stability and high sensitivity in high-field DEER measurements. The high sensitivity of the Gd(3+) ion is associated with its high spin (S = 7/2) and small zero field splitting (ZFS), resulting in a narrow spectral width of its central transition at high fields. However, under the conditions of short distances and exceptionally small ZFS, the weak coupling approximation, which is essential for straightforward DEER data analysis, becomes invalid and the pseudo-secular terms of the dipolar Hamiltonian can no longer be ignored. This work further explores the effects of pseudo-secular terms on Gd(3+)-Gd(3+) DEER measurements using a specifically designed ruler molecule; a rigid bis-Gd(3+)-DOTA model compound with an expected Gd(3+)-Gd(3+) distance of 2.35 nm and a very narrow central transition at the W-band (95 GHz). We show that the DEER dipolar modulations are damped under the standard W-band DEER measurement conditions with a frequency separation, Δν, of 100 MHz between the pump and observe pulses. Consequently, the DEER spectrum deviates considerably from the expected Pake pattern. We show that the Pake pattern and the associated dipolar modulations can be restored with the aid of a dual mode cavity by increasing Δν from 100 MHz to 1.09 GHz, allowing for a straightforward measurement of a Gd(3+)-Gd(3+) distance of 2.35 nm. The increase in Δν increases the contribution of the |-5/2〉→|-3/2〉 and |-7/2〉→|-5/2〉 transitions to the signal at the expense of the |-3/2 〉→|-1/2〉 transition, thus minimizing the effect of dipolar pseudo-secular terms and restoring the validity of the weak coupling approximation. We apply this approach to the A93C/N140C mutant of T4 lysozyme labeled with two different Gd(3+) tags that have narrow central transitions and show that even for a distance of 4 nm there is still a significant (about two-fold) broadening that is removed by increasing Δν to 636 MHz and 898 MHz.

The effects of ester addition on nanostructural properties of biodegradable ILs composed of 1-alkoxycarbonyl-3-alkyl-imidazolium cations ([C1COOCnC1im](+), n = 1, 2, 4) combined with [Br](-), [NO3](-), [BF4](-), [PF6](-), [TfO](-), and [Tf2N](-) were explored by using the molecular dynamics (MD) simulations and quantum theory of atoms in molecules (QTAIM) analysis at 400 K. Various thermodynamic properties of these ILs were extensively computed in our earlier work (Ind. Eng. Chem. Res., 2015, 54, 11678-11700). Nano-scale segregation analysis demonstrates the formation of a small spherical island-like hydrocarbon within the continuous ionic domain for ILs with short alkyl side chain ([C1COOC1C1im]), and a sponge-like nanostructure for the compound with long alkyl side chain ([C1COOC4C1im]). Ester-functionalized ILs with ethyl side chain ([C1COOC2C1im]) are the turning point between two different morphologies. Non-polar channels were observed for [C1COOC4C1im] ILs composed of smaller anions such as [Br] and [NO3], whereas clustering organization was found for the other anions. Formation of the spherical micelle-like nanostructure was seen for lengthened cations. Finally, the incorporation of an ester group into the alkyl side chain of the cation leads to stronger segregation between charged and uncharged networks, which consequently increased the possibility of self-assembly and micelle formation.

The insertion of 1-octyl-3-methylimidazolium cations (OMIM(+)) from a diluted aqueous ionic liquid (IL) solution into a model of a bacterial cell membrane is investigated. Subsequently, the mutual interactions of cations inside the membrane and their combined effect on membrane properties are derived. The ionic liquid solution and the membrane model are simulated using molecular dynamics in combination with empirical force fields. A high propensity of OMIM(+) for membrane insertion is observed, with a cation concentration at equilibrium inside the membrane 47 times larger than in the solvent. Once inserted, cations exhibit a weak effective attraction inside the membrane at a distance of 1.3 nm. At this free energy minimum, negatively charged phosphates of the phospholipids are sandwiched between two OMIM(+) to form energetically favorable OMIM(+)-phosphate-OMIM(+) types of coordination. The cation-cation association free energy is 5.9 kJ mol(-1), whereas the activation barrier for dissociation is 10.1 kJ mol(-1). Subsequently, OMIM(+) are inserted into the leaflet of the membrane bilayer that represents the extracellular side. The cations are evenly distributed with mutual cation distances according to the found optimum distance of 1.3 nm. Because of the short length of the cation alkyl chains compared to lipid fatty acids, voids are generated in the hydrophobic core of the membrane. These voids disorder the fatty acids, because they enable fatty acids to curl into these empty spaces and also cause a thinning of the membrane by 0.6 nm. Additionally, the membrane density increases at its center. The presence of OMIM(+) in the membrane facilitates the permeation of small molecules such as ammonia through the membrane, which is chosen as a model case for small polar solutes. The permeability coefficient of the membrane with respect to ammonia increases substantially by a factor of seven. This increase is caused by a reduction of the involved free energy barriers, which is effected by the cations through the thinning of the membrane and favorable interactions of the delocalized OMIM(+) charge with ammonia inside the membrane. Overall, the results indicate the antimicrobial effect of amphiphilic imidazolium-based cations that are found in various common ILs. This effect is caused by an alteration of the permeability of the bacterial membrane and other property changes.

Cation-π interactions are common in biological systems, and many structural studies have revealed the aromatic box as a common motif. With the aim of understanding the nature of the aromatic box, several computational methods were evaluated for their ability to reproduce experimental cation-π binding energies. We find the DFT method M06 with the 6-31G(d,p) basis set performs best of several methods tested. The binding of benzene to a number of different cations (sodium, potassium, ammonium, tetramethylammonium, and guanidinium) was studied. In addition, the binding of the organic cations NH4(+) and NMe4(+) to ab initio generated aromatic boxes as well as examples of aromatic boxes from protein crystal structures were investigated. These data, along with a study of the distance dependence of the cation-π interaction, indicate that multiple aromatic residues can meaningfully contribute to cation binding, even with displacements of more than an angstrom from the optimal cation-π interaction. Progressive fluorination of benzene and indole was studied as well, and binding energies obtained were used to reaffirm the validity of the "fluorination strategy" to study cation-π interactions in vivo.

Guanine radical cations are formed upon oxidation of DNA. Deoxyguanosine (dG) is used as a model, and the gas-phase infrared (IR) spectroscopic signature and gas-phase unimolecular and bimolecular chemistry of its radical cation, dG˙(+), A, which is formed via direct electrospray ionisation (ESI/MS) of a methanolic solution of Cu(NO3)2 and dG, are examined. Quantum chemistry calculations have been carried out on 28 isomers and comparisons between their calculated IR spectra and the experimentally-measured spectra suggest that A exists as the ground-state keto tautomer. Collision-induced dissociation (CID) of A proceeds via cleavage of the glycosidic bond, while its ion–molecule reactions with amine bases occur via a number of pathways including hydrogen-atom abstraction, proton transfer and adduct formation. A hidden channel, involving isomerisation of the radical cation via adduct formation, is revealed through the use of two stages of CID, with the final stage of CID showing the loss of CH2O as a major fragmentation pathway from the reformed radical cation, dG˙(+). Quantum chemistry calculations on the unimolecular and bimolecular reactivity are also consistent with A being present as a ground-state keto tautomer.

The reactions of FeO(+) with H2 and of Fe(+) with N2O were studied with respect to the production and reactivity of electronically excited (4)Fe(+) cations. The reaction of electronic ground state (6)FeO(+) with H2 was found to predominantly produce electronically excited (4)Fe(+) as opposed to electronic ground state (6)Fe(+) corresponding to a spin-allowed reaction. (4)Fe(+) was observed to react with N2O with a rate constant of 2.3 (+0.3/-0.8) × 10(-11) cm(3) molecule(-1) s(-1), smaller than the ground state (6)Fe(+) rate constant of 3.2 (±0.5) × 10(-11) cm(3) molecule(-1) s(-1) (at room temperature). While the overall reaction of (6)FeO(+) with H2 within the Two-State-Reactivity concept is governed by efficient sextet-quartet spin-inversion in the initial reaction complex, the observation of predominant (4)Fe(+) production in the reaction is attributed to a much less efficient quartet-sextet back-inversion in the final reaction complex. Average spin-inversion probabilities are estimated by statistical modeling of spin-inversion processes and related to the properties of spin-orbit coupling along the reaction coordinate. The reaction of FeO(+) with H2 served as a source for (4)Fe(+), subsequently reacting with N2O. The measured rate constant has allowed for a more detailed understanding of the ground state (6)Fe(+) reaction with N2O, leading to a significantly improved statistical modeling of the previously measured temperature dependence of the reaction. In particular, evidence for the participation of electronically excited states of the reaction complex was found. Deexcitation of (4)Fe(+) by He was found to be slow, with a rate constant <3 × 10(-14) cm(3) molecule(-1) s(-1).

The photophysical properties of 5-deazaalloxazine and 1,3-dimethyl-5-deazalloxazine at different pH values were characterized using absorption spectra, fluorescence emission spectra, fluorescence excitation spectra, synchronous fluorescence spectra and total fluorescence spectra. Their ionised and/or neutral forms were discussed in comparison with those obtained for other derivatives of 5-deazaalloxazine and/or 5-deazaisoalloxazine. Steady-state and time-resolved techniques were used to study the protonation/deprotonation equilibria between cationic and neutral forms of both compounds and between neutral and monoanionic forms of 5-deazalloxazine, as well as between monoanionic forms of this compound and its dianion. We estimated pKa values for these equilibria both in the ground and excited states. Our steady-state and time-resolved measurements indicate that the cation of 5-deazaalloxazine in its isoalloxazinic form exhibits fluorescence that is quenched by protons in a dynamic process. Contrary to that, the cation of 1,3-dimethyl-5-deazaalloxazine has almost no fluorescence. Additionally, we found that the neutral forms of 5-deazalloxazine and 1,3-methyl-5-deazalloxazine are also quenched in acidic conditions by protons. In basic conditions, 5-deazaalloxazine forms two structurally different anions, namely the alloxazinic monoanion and the isoalloxazinic monoanion; both simultaneously dissociate into the isoalloxazinic dianion at even higher pH values. The synchronous fluorescence spectra and total fluorescence spectra demonstrated their suitability to characterize and differentiate different fluorescent forms of 5-deazalloxazine, namely: the cation, the neutral form, two monoanions, and the dianion, in a wide pH range.