Stable Hydrogen Bonds Research Articles

Structural Changes of Sarco/Endoplasmic Reticulum Ca2+-ATPase Induced by Rutin Arachidonate: A Molecular Dynamics Study.

Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) maintains the level of calcium concentration in cells by pumping calcium ions from the cytoplasm to the lumen while undergoing substantial conformational changes, which can be stabilized or prevented by various compounds. Here we attempted to clarify the molecular mechanism of action of new inhibitor rutin arachidonate, one of the series of the acylated rutin derivatives. We performed molecular dynamics simulations of SERCA1a protein bound to rutin arachidonate positioned in a pure dipalmitoylphosphatidylcholine bilayer membrane. Our study predicted the molecular basis for the binding of rutin arachidonate towards SERCA1a in the vicinity of the binding site of calcium ions and near the location of the well-known inhibitor thapsigargin. The stable hydrogen bond between Glu771 and rutin arachidonate plays a key role in the binding. SERCA1a is kept in the E2 conformation preventing the formation of important salt bridges between the side chains of several residues, primarily Glu90 and Lys297. All in all, the structural changes induced by the binding of rutin arachidonate to SERCA1a may shift proton balance near the titrable residues Glu771 and Glu309 into neutral species, hence preventing the binding of calcium ions to the transmembrane binding sites and thus affecting calcium homeostasis. Our results could lead towards the design of new types of inhibitors, potential drug candidates for cancer treatment, which could be anchored to the transmembrane region of SERCA1a by a lipophilic fatty acid group.

The Structural Origin of Cholesterol Induced Phosphoinositide Clustering

Phosphoinositide lipids (PIPs) are important mediators for an extraordinary array of cellular functions. Many of these cellular events are sensitive to cholesterol depletion and it has been speculated that PIPs are raft associated. However, the stearoyl/arachidonoyl acyl chain composition of PIPs is generally unfavorable for an accumulation in a liquid-ordered (lo) environment and PIPs fail to enrich in such phases. Nevertheless, cholesterol promotes PIP domain formation in ternary PC/PIP/cholesterol lipid mixtures. To elucidate the structural origins of the PIP/cholesterol interaction, we have conducted all-atom simulations of PI(4,5)P2/cholesterol monolayers and validated our results using surface pressure/area experiments of Langmuir films. In contrast to PC monolayers, we find for PI(4,5)P2 monolayers that cholesterol interacts significantly with the headgroups. On average, 20-25% of the cholesterol hydroxyl groups form hydrogen bonds with the PIP phosphodiester and the C2 and C6-hydroxyl groups of the inositol rings. The participation of cholesterol in the PIP headgroup hydrogen bond network leads to a stabilization of the PIP enriched domain. The inositol ring tilt angle (relative to the surface normal) is reduced in the presence of cholesterol. Furthermore, the acyl chain tilt angle is decreased and the acyl chain order is increased. While lo phase (raft) domain formation is governed by the interaction of cholesterol with lipid chains; the origin of PIP domain formation is fundamentally different: it is the result of the participation of cholesterol in the intermolecular hydrogen bond network formed within the PIP headgroup region. This cholesterol stabilized hydrogen bond network is particularly sensitive to ion effects. Na+ stabilizes the intermolecular hydrogen bond networks, while this is less pronounced for K+. Ca2+ and cholesterol synergistically promote PIP domain formation.

Synthesis, biological evaluation and molecular modeling study of 2-amino-3,5-disubstituted-pyrazines as Aurora kinases inhibitors

Serine/threonine protein kinases Aurora A, B, and C play essential roles in cell mitosis and cytokinesis, and a number of Aurora kinase inhibitors have been evaluated in the clinic. Herein we report the synthesis and their antiproliferation of 3,5-disubstituted-2-aminopyrazines as kinases inhibitors. Amongst, 4-((3-amino-6- (3,5-dimethylisoxazol-4-yl)pyrazin-2-yl)oxy)-N-(3-chlorophenyl) benzamide (12Aj) exhibited the strongest antiproliferative activities against U38, HeLa, HepG2 and LoVo cells with IC50 values were 11.5 ± 3.2, 1.34 ± 0.23, 7.30 ± 1.56 and 1.64 ± 0.48 μM, as well as inhibited Aurora A and B with the IC50 values were 90 and 152 nM, respectively. Molecular docking studies indicated that 12Aj appeared to form stable hydrogen bonds with either Aurora A or Aurora B. Furthermore, 12Aj arrested HeLa cell cycle in G2/M phase by regulating protein levels of cyclinB1 and cdc2. In addition, the bioinformatics prediction further revealed that 12Aj possessed good drug likeness using SwissADME. These results suggested that 12Aj was worthy of future development of potent anticancer agents as pan-Aurora kinases.

Predicting interfacial hot-spot residues that stabilize protein-protein interfaces in oligomeric membrane-toxin pores through hydrogen bonds and salt bridges

Pore forming toxins (PFTs) are proteins which form unregulated oligomeric pores on target plasma membranes to cause ion leakage and cell death and represent the largest class of bacterial virulence factors. With increasing antibiotic-resistant bacterial strains, alternate therapies are being developed to target toxin pore formation rather than the bacteria themselves. One strategy is to undermine the stability of these multimeric pores, whose subunits are held together by complex amino acid interaction networks, by identifying key residues in these networks which could be plausible drug or mutagenesis targets. However, this requires a quantitative assessment of per residue contributions towards pore stability, which cannot be reliably gleaned from static crystal/cryo-EM pore structures. In this study, we overcome this limitation by developing a computational screening algorithm that employs fully atomistic molecular dynamics simulations coupled with energy-based screening that can predict ‘hot-spot’ residues which engage in persistent and stabilizing hydrogen bonds or salt bridges across protein-protein interfaces. Application of this algorithm to prototypical α-PFT (cytolysin A) and β-PFT (α-hemolysin) membrane-inserted pores yielded a small predicted set of highly interacting residues, blocking of which could destabilize pore complexes. Previous mutagenesis studies validate some of our in silico predictions. The algorithm could be applied to all pores with known structures to generate a database of destabilizing mutations, which could then serve as a basis for experimental validation and rational structure-based inhibitor design.Communicated by Ramaswamy H. Sarma

Inhibition Mechanism of Indoleamine 2, 3-Dioxygenase 1 (IDO1) by Amidoxime Derivatives and Its Revelation in Drug Design: Comparative Molecular Dynamics Simulations.

For cancer treatment, in addition to the three standard therapies of surgery, chemotherapy, and radiotherapy, immunotherapy has become the fourth internationally-recognized alternative treatment. Indoleamine 2, 3-dioxygenase 1 (IDO1) catalyzes the conversion of tryptophan to kynurenine causing lysine depletion, which is an important target in the research and development of anticancer drugs. Epacadostat (INCB024360) is currently one of the most potent IDO1 inhibitors, nevertheless its inhibition mechanism still remains elusive. In this work, comparative molecular dynamics simulations were performed to reveal that the high inhibitory activity of INCB024360 mainly comes from two aspects: disturbing the ligand delivery tunnel and then preventing small molecules such as oxygen and water molecules from accessing the active site, as well as hindering the shuttle of substrate tryptophan with product kynurenine through the heme binding pocket. The scanning of key residues showed that L234 and R231 residues both were crucial to the catalytic activity of IDO1. With the association with INCB024360, L234 forms a stable hydrogen bond with G262, which significantly affects the spatial position of G262-A264 loop and then greatly disturbs the orderliness of ligand delivery tunnel. In addition, the cleavage of hydrogen bond between G380 and R231 increases the mobility of the GTGG conserved region, leading to the closure of the substrate tryptophan channel. This work provides new ideas for understanding action mechanism of amidoxime derivatives, improving its inhibitor activity and developing novel inhibitors of IDO1.

Biological evaluation and interaction mechanism of beta-site APP cleaving enzyme 1 inhibitory pentapeptide from egg albumin

Inhibition of beta-site APP cleaving enzyme1 (BACE1) is one of the most promising therapeutic approaches for Alzheimer’s disease. To find natural products for the treatment of Alzheimer's disease, absorption, distribution, metabolism, excretion and toxicity (ADMET) properties and in vitro BACE1 inhibitory activity of the peptides isolated from egg albumin were evaluated. Then, molecular docking and molecular dynamics simulation were used to explain the molecular mechanism of the interactions between BACE1 and peptides. The IC50 value of peptide KLPGF, with satisfactory ADMET properties, against BACE1 was (8.30 ± 0.56) mmol/L. Molecular docking revealed that KLPGF contacted with the residues of BACE1’s active sites through twelve hydrogen bonds interactions, two hydrophobic interactions, one electrostatic interaction, and two Pi-cation interactions. The 5 ns molecular dynamics simulations confirmed that the structure of KLPGF with BACE1 was stable. Peptide KLPGF contacted the residues Lys321, Asp228, and Asn233 with stable hydrogen bonds. KLPGF may be a potential anti-BACE1 candidate.

Predicting partition coefficients of drug-like molecules in the SAMPL6 challenge with Drude polarizable force fields.

The water-octanol partition coefficient is an important physicochemical property for small molecule drug design. Here, we report our participation in the SAMPL6 logP prediction challenge with free energy perturbation (FEP) calculations in the water phase and in the 1-octanol phase using Drude polarizable force fields. Root mean square error (RMSE) and mean absolute error (MAE) of our prediction are equal to 1.85 and 1.25 logP units. The errors are not evenly distributed. Out of eleven SAMPL6 solutes, FEP/Drude performed very badly on three molecules (deviations all larger than 2 logP units) but good on the remaining eight (deviations all less than 1 logP unit). We find while FEP converges well within one nanosecond in water, simulations in 1-octanol need much longer simulation time and possibly more independent runs for sampling. We also find out that 1-octanol, albeit being a non-polar solvent, still polarizes solute molecules and forms stable hydrogen bonds with them. At the end, we attempt to reweight FEP trajectories with QM/Drude calculations and discuss possible caveats in our simulation setup.

Tunable polymorph and morphology synthesis of iron oxalate nanoparticles as anode materials for lithium ion batteries

Iron oxalate (FeC2O4), a promising anode material for lithium ion batteries (LIBs), is typically crystallized in orthorhombic-type phase. When the synthesis temperature rises, β-FeC2O4·H2O can transform into high-crystalline α-phase. At present, the detail evolution mechanism of crystal structure for two kinds of iron oxalate polymorphs is seldom studied. Through in-depth experiments, the tunable polymorph and morphology of iron oxalate can be obtained by controlling certain conditions. The oxalic acid complex ([Fe(C2O4) x]−2(x−1)), as unstable intermediate state, can change the reaction thermodynamics and kinetics, thus promoting the nucleation and growth of crystals. Higher temperature and longer reaction time would availably reinstitute stable hydrogen bonds and enhance the disordered state between successive stack layers, then resulting in various morphologies and phase-transition process. Due to short diffusion path and stable effective channels for Li+ ions, the mixed state of iron oxalate exhibits higher reversible capacity and more excellent cycling stability. Understanding the phase evolution mechanism of iron oxalate is critical to controllable synthesis, and ultimately, enhancing the performance of future LIBs.

Crystal engineering of exemestane to obtain a co-crystal with enhanced urease inhibition activity.

Co-crystallization is a phenomenon widely employed to enhance the physio-chemical and biological properties of active pharmaceutical ingredients (APIs). Exemestane, or 6-methyl-ideneandrosta-1,4-diene-3,17-dione, is an anabolic steroid used as an irreversible steroidal aromatase inhibitor, which is in clinical use to treat breast cancer. The present study deals with the synthesis of co-crystals of exemestane with thio-urea by liquid-assisted grinding. The purity and homogeneity of the exemestane-thio-urea (1:1) co-crystal were confirmed by single-crystal X-ray diffraction followed by thermal stability analysis on the basis of differential scanning calorimetry and thermogravimetric analysis. Detailed geometric analysis of the co-crystal demonstrated that a 1:1 co-crystal stoichiometry is sustained by N-H⋯O hydrogen bonding between the amine (NH2) groups of thio-urea and the carbonyl group of exemestane. The synthesized co-crystal exhibited potent urease inhibition activity in vitro (IC50 = 3.86 ± 0.31 µg ml-1) compared with the API (exemestane), which was found to be inactive, and the co-former (thio-urea) (IC50 = 21.0 ± 1.25 µg ml-1), which is also an established tested standard for urease inhibition assays in vitro. The promising results of the present study highlight the significance of co-crystallization as a crystal engineering tool to improve the efficacy of pharmaceutical ingredients. Furthermore, the role of various hydrogen bonds in the crystal stability is successfully analysed quantitatively using Hirshfeld surface analysis.

Anomalous proton conduction behavior across a nanoporous two-dimensional conjugated aromatic polymer membrane.

We investigate aqueous proton penetration behavior across a newly synthesized nanoporous two-dimensional conjugated aromatic polymer (2D-CAP) membrane using extensive ReaxFF reactive molecular dynamics simulations. We found that the proton penetration energy barrier across 2D-CAP is twice as high as that of graphtetrayne, even though 2D-CAP exhibits a larger pore size. Detailed analysis indicates that the anomalous high proton conduction energy barrier of 2D-CAP originates from its unique atomic nanopore structure. The hydrogen atoms at the periphery of the 2D-CAP nanopores can form a stable local hydrogen bond network with water molecules inside or surrounding the nanopores. The mobility of water molecules involved in this local hydrogen bond network will be significantly lowered, and the proton transportation process across the nanopores will thus be impeded. Our results show that the proton penetration behavior across nanoporous 2D materials is influenced not only by the pore size, but also by the decorated atoms or functional groups at the pore edges. Hydrogen atoms at the periphery of nanopores with certain geometry can form a stable local hydrogen bond network with neighboring water molecules, further hampering the proton conductivity.

Counterintuitive torsional barriers controlled by hydrogen bonding.

The torsional barriers along the Caryl-Caryl axis of a pair of isosteric disubstituted biphenyls were determined by variable temperature 1H NMR spectroscopy in three solvents with contrasted hydrogen bond accepting abilities (1,1,2,2-tetrachloroethane-d2, nitrobenzene-d5 and dimethyl sulfoxide-d6). One of the biphenyl scaffolds was substituted at its ortho and ortho' positions with N'-acylcarbohydrazide groups that could engage in a pair of intramolecular N-HO=C hydrogen bonding interactions at the ground state, but not at the transition state of the torsional isomerization pathway. The torsional barrier of this biphenyl was exceedingly low despite the presence of the hydrogen bonds (16.1, 15.6 and 13.4 kcal mol-1 in the three aforementioned solvents), compared to the barrier of the reference biphenyl (15.3 ± 0.1 kcal mol-1 on average). Density functional theory and the solvation model developed by Hunter were used to decipher the various forces at play. They highlighted the strong stabilization of hydrogen bond donating solutes not only by hydrogen bond accepting solvents, but also by weakly polar, yet polarizable solvents. As fast exchanges on the NMR time scale were observed above the melting point of dimethyl sulfoxide-d6, a simple but accurate model was also proposed to extrapolate low free activation energies in a pure solvent (dimethyl sulfoxide-d6) from higher ones determined in mixtures of solvents (dimethyl sulfoxide-d6 in nitrobenzene-d5).

Studies on Substituted Thienopyridine Carbonitriles as Src Inhibitors Using a Comprehensive In Silico Method

To explore the structural requirements and inhibitory mechanism of Src inhibitors, the comparative molecular field analysis, comparative molecular similarity indices analysis and three-dimensional quantitative structure-activity relationship and molecular docking of 45 substituted thienopyridine carbonitriles as tyrosine kinase pp60src inhibitors was conducted. Three three-dimensional quantitative structure-activity relationship models showed high predictabilities with cross-validated correlation coefficient and predictive correlation coefficient values of 0.793 and 0.887 for comparative molecular field analysis and 0.624 and 0.793 for comparative molecular similarity indices analysis, respectively. Docking results indicated that 4 compounds with high inhibitory activity penetrated into the active pocket of tyrosine kinase pp60src and formed stable hydrogen bonds with the binding pocket of tyrosine kinase pp60src. Leu273, Lys295, Thr338, Asp348, and Ser345 of tyrosine kinase pp60src are important residues. The results could be of great value in designing novel substituted thienopyridine carbonitriles with more potent Src kinase inhibitory activity.

Design, synthesis and in vitro biological evaluation of quinazolinone derivatives as EGFR inhibitors for antitumor treatment

In this paper, a series of novel 3-methyl-quinazolinone derivatives was designed, synthesised and evaluated for antitumor activity in vitro on wild type epidermal growth factor receptor tyrosine kinase (EGFRwt-TK) and three human cancer cell lines including A549, PC-3, and SMMC-7721. The results displayed that some of the compounds had good activities, especially 2-{4-[(3-Fluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5 g), 2-{4-[(3,4-Difluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5k) and 2-{4-[(3,5-Difluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5 l) showed high antitumor activities against three cancer cell lines. Moreover, compound 5k could induce late apoptosis of A549 cells at high concentrations and arrest cell cycle of A549 cells in the G2/M phase at tested concentrations. Also, compound 5k could inhibit the EGFRwt-TK with IC50 value of 10 nM. Molecular docking data indicates that the compound 5k may exert inhibitory activity by forming stable hydrogen bonds with the R817, T830 amino acid residues and cation-Π interaction with the K72 residue of EGFRwt-TK.

Construction of stable hydrogen bonds at high temperature for preparation of polyimide films with ultralow coefficient of thermal expansion and high Tg

Low coefficient of thermal expansion (CTE) in the range of 40–400 °C is a crucial factor for polyimide (PI) films serving as the flexible substrate for display devices. The introduction of hydrogen bonds (H-bonds) is an effective method to obtain high Tg and low in-plane CTE below polyimide (PI) film. However, these H-bonds commonly exhibit low thermal stability and would be ruptured at high temperature (>300 °C), which leads to a remarkable increase of CTE. Herein, we report a strategy to improve thermal stability of H-bonds at the high temperature via intermolecular crosslinking. For neat PI, its in-situ FTIR results confirm severe dissociation of H-bonds above 300 °C, While after the crosslinking reaction, the content of strong H-bonds at 400 °C is 110% higher than that of neat PI, which indicates this intermolecular crosslinking restrains dissociation of H-bonds. Correspondingly, CTE values of crosslinked PI films at 300oC–400 °C are sharply decreased from 33.8 ppm/K to 6.0 ppm/K. Moreover, decrease of in-plane orientation accompanying lower CTEs in crosslinked PI deviates from common rule reported in linear PIs, implying the important roles of H-bonds and crosslinking. More over, the contribution of H-bonds and crosslink to the decrease of CTE are performed by Pearson correlation analysis and the results indicate that the decrease of CTE in crosslinked PIs at low temperatures is completely attributed to confinement effect of crosslinking, but contribution of stable H-bonds becomes more prominent above 300 °C. Consequently, the obtained PI films exhibit ultra low CTE (1.9 ppm/K) at the range of 40oC–400 °C, along with high Tg (>450 °C) exhibiting great potential for flexible-display substrates.

Molecular dynamics and computational study of Mannich-based coumarin derivatives: potent tyrosine kinase inhibitor

The manifestation of bacterial UTI (Urinary Tract Infection) has been predominantly endemic, globally; eventually, the development of new UTI antibacterial agent(s) remains the call of the day. Herein, two series of Mannich-based 4-hydroxy coumarin derivatives, 7a-m and 8a-m were designed by suitable heterocyclic amines condensed with aldehydes. The synthesised molecules were interpreted by 1H-NMR and 13C-NMR spectral analyses with in vitro antibacterial studies. The compound, 4-hydroxy-3-((4-hydroxy-3-methoxyphenyl)(morpholino)methyl)-2H-chromen-2-one 8l was the significant derivative against pathogenic bacteria Staphylococcus aureus and Escherichia coli with MIC values 12.50 and 25 µM, respectively. Computational assessments with the Lipinski’s rule of five, ADMET properties and molecular docking studies revealed that analogues, 7f, 7l, 8d, 8j and 8k could be potent druggable molecules with significant binding affinity towards bacterial tyrosine kinase, as target. To understand the mode of binding and intrinsic stabilities of potent receptor-ligand complexes, each system was subjected molecular dynamics simulations for 100 ns. Inter-molecular contact analysis and intrinsic hydrogen-bond stability portrayed the analogues 8l form a number of non-bonded contacts with the receptor tyrosine kinase being mostly dominated by electrostatic and hydrophobic contacts. The results from the present structure-based designing approach might be a valuable tool towards identification of a new antibacterial drug candidate(s) against UTI in near future.Abbreviations4-HC4-hydroxy coumarinADMETabsorption, distribution, metabolism, excretion, toxicityDCE1,2-dichloroethaneDCMdichloromethaneDMSOdimethyl sulfoxideMDmolecular dynamicsMICminimum inhibitory concentrationNMRnuclear magnetic resonanceNPTisothermal isobaric ensemblesNVTcanonical ensemblesPCAprincipal component analysisPDBprotein data bankRgradius gyrationRMSFroot-mean-square fluctuationsRSMDroot-mean-square deviationUTIurinary Tract InfectionCommunicated by Ramaswamy H. Sarma

In Situ Defect Passivation with Silica Oligomer for Enhanced Performance and Stability of Perovskite Solar Cells

AbstractPerovskite solar cells (PVSCs) have achieved excellent power conversion efficiency (PCE) but still suffer from instability issues. Defect passivation is an important route to simultaneously increase the efficiency and stability of PVSCs. Here, a strategy of incorporating silica oligomer in perovskite films for surface and grain boundary defect passivation is reported. Silica oligomer passivation agent (PA) is in situ formed through hydrolysis and condensation reaction of tetraethyl orthosilicate additive in perovskite precursor. The passivation mechanism is elucidated by density functional theory calculation, revealing stable chelating interaction and hydrogen bond interaction between PA and perovskite. Spectroscopic and electrical characterizations demonstrate that silica oligomer can enlarge grain sizes, prolong carrier lifetime, enhance charge carrier dynamics, and reduce trap state densities in perovskite films. Planar PVSCs with passivation achieve a highly improved PCE of 19.64% with a stabilized efficiency of 18.81%. More importantly, unencapsulated perovskite devices with passivation retain nearly 90% of original efficiency after 1000 h storage under ambient condition and sustained 87% of initial performance after high‐temperature (120 °C) thermal accelerated aging, showing highly enhanced moisture and thermal stability. Therefore, the present study provides a pathway to the future design and optimization of PVSCs with higher efficiency and greater stability.

Zeolite Structure Direction: Identification, Strength and Involvement of Weak CH⋅⋅⋅O Hydrogen Bonds.

We demonstrate that weak CH⋅⋅⋅O hydrogen bonds (HBs) are important host-guest interactions in zeolite assemblies involving structure directing organocations. This type of HB is identified between alkyl groups of the organic structure directing agent (OSDA) and the silica framework in as-synthesized silicalite-1 of complex topology (MFI) using a combination of experimental and theoretical data obtained at low and room temperatures. The 28 weak CH⋅⋅⋅O HBs, evidenced along dynamics simulation at room temperature, represent 30 % of the energy of the Coulomb electrostatic interaction between OSDA and the zeolite framework. The strongest and most stable HB found here connects the OSDA to the [41 52 62 ] cage containing F atoms and should contribute to preserve zeolite topology during crystal growth. An inspection of other as-synthesized zeolites of very different framework topology indicates that the directional CH⋅⋅⋅O HBs have to be considered when discussing zeolite structure directing phenomena.

Comments on chemical properties reported for diphenyl disulfide and its derivatives: The merit of the phenyl groups

AbstractThe symmetrical 2,2′‐disubstitued derivatives of diphenyl disulfide showing widely spanning rates of electrophilic attack of the HIV‐1 nucleocapsid protein p7 zinc fingers have been rationalized, based on the lowest unoccupied molecular orbital (LUMO)‐lowering approach, by the substituents' π‐effects and the hydrogen bond stabilization effects. In the 2,2′‐amide‐ and 4,4′‐N‐amide‐substituted derivatives, the extent of LUMO lowering has been reduced by the destabilization of lone‐pair bond orbital, lp(N), present on the nitrogen atom of N‐amide. From the natural bond orbital viewpoint, hydrogen bond stabilization of LUMO is mainly governed by stabilization of the σ*SS bond orbital.

High-resolution EPR distance measurements on RNA and DNA with the non-covalent Ǵ spin label.

Pulsed electron paramagnetic resonance (EPR) experiments, among them most prominently pulsed electron-electron double resonance experiments (PELDOR/DEER), resolve the conformational dynamics of nucleic acids with high resolution. The wide application of these powerful experiments is limited by the synthetic complexity of some of the best-performing spin labels. The recently developed n}{}bfacute{G} (G-spin) label, an isoindoline-nitroxide derivative of guanine, can be incorporated non-covalently into DNA and RNA duplexes via Watson-Crick base pairing in an abasic site. We used PELDOR and molecular dynamics (MD) simulations to characterize n}{}bfacute{G}, obtaining excellent agreement between experiments and time traces calculated from MD simulations of RNA and DNA double helices with explicitly modeled n}{}bfacute{G} bound in two abasic sites. The MD simulations reveal stable hydrogen bonds between the spin labels and the paired cytosines. The abasic sites do not significantly perturb the helical structure. n}{}bfacute{G} remains rigidly bound to helical RNA and DNA. The distance distributions between the two bound n}{}bfacute{G} labels are not substantially broadened by spin-label motions in the abasic site and agree well between experiment and MD. n}{}bfacute{G} and similar non-covalently attached spin labels promise high-quality distance and orientation information, also of complexes of nucleic acids and proteins.

Study of solvation of substituted propylbenzene in ethanol-water solutions under subcritical conditions by molecular dynamics

Solutions of 2-methoxy-4-(2′-hydroxypropyl)phenol (PrPh) in water and water-ethanol mixtures (0.020, 0.115, 0.285 mol fraction of ethanol) at temperature 573 K and densities corresponding to an experimental pressure of 23 MPa have been simulated by molecular dynamics. Distribution of components in the fluid bulk and in the PrPh solvate shell has been researched. Numbers and lifetimes of hydrogen bonds between the components have been determined, and tendencies to selective solvation have been analyzed. It has been shown that PrPh molecules form stable long-lived hydrogen bonds with water and ethanol. An increase in ethanol concentration leads to a decrease in the number of hydrogen bonds formed by PrPh and to an increase in their lifetime that indicates growing stability of the solvate complexes. The local mole fraction of ethanol around PrPh is lower than its average mole fraction in the fluid, i.e., the PrPh solvate shells mainly consist of water molecules.