Discrete Water Molecules Research Articles

Theoretical Investigations of State Specific Hydrogen Atom Transfer in 8-Formyl-7-hydroxy-4-methylcoumarin

Excited state intramolecular hydrogen transfer (ESIHT) reaction of 8-formyl-7-hydroxy-4-methyl coumarin (FC) in its pure and hydrated state FC-(H2O)4 (FCH) has been studied by implementing state specific time dependent density functional theory (SS-TDDFT) along with the effective fragment potential (EFP1) method for solvation with discrete water molecules. The intramolecular hydrogen bond formed between hydroxyl hydrogen (H18) and formyl oxygen (O15) and intermolecular hydrogen bonds formed due to microsolvation were explored. The studies of electrostatic potential, natural charge analysis, difference electron density map and UV-Vis spectra of both FC and FCH molecules establish the intramolecular charge transfer (ICT) states of the molecules. The vertical excitation from S0 to S1 state causes the transfer of hydroxyl hydrogen to formyl oxygen and from S1 to S3 causes the transfer of the hydrogen atom back to hydroxyl oxygen. Potential energy surface scans along intramolecular hydrogen bonding at the ground and excited states confirm the state specific ESIHT reaction in both FC and FCH molecules.

Just Add Water: Modulating the Structure-Derived Acidity of Catalytic Hexameric Resorcinarene Capsules.

The hexameric undecyl-resorcin[4]arene capsule (C11R6) features eight discrete structural water molecules located at the vertices of its cubic suprastructure. Combining NMR spectroscopy with classical molecular dynamics (MD), we identified and characterized two distinct species of this capsule, C11R6-A and C11R6-B, respectively featuring 8 and 15 water molecules incorporated into their respective hydrogen-bonded networks. Furthermore, we found that the ratio of the C11R6-A and C11R6-B found in solution can be modulated by controlling the water content of the sample. The importance of this supramolecular modulation in C11R6 capsules is highlighted by its ability to perform acid-catalyzed transformations, which is an emergent property arising from the hydrogen bonding within the suprastructure. We show that the conversion of C11R6-A to C11R6-B enhances the catalytic rate of a model Diels–Alder cyclization by 10-fold, demonstrating the cofactor-derived control of a supramolecular catalytic process that emulates natural enzymatic systems.

Theoretical Study of the Microhydration the Chemical Warfare Agent Sulfur Mustard.

A microhydration study of sulfur mustard (SM) was carried out using M06-2X, B3LYP, B3LYP-D3, and MP2 levels of theory with the 6-311++G(2d,2p) basis set. The changes in energetics, structural parameters and vibrational wavenumbers following the addition of up to three discrete water molecules to SM were analyzed. We observed slight changes in the geometry of SM upon microhydration. The stability of hydrated clusters is due to weak C–H···O–H hydrogen bonds. The free energy change for the formation of the clusters is positive at room temperature and becomes exergonic when the temperature decreases. The infrared stretchings of C–Cl of SM and O–H of water are redshifted upon the addition of water molecules. The findings from this work add to the literature of hydrated SM and can be useful in its detection and subsequent destruction.

•OH oxidation of methionine in the presence of discrete water molecules: DFT, QTAIM and valence bond analyses

The first steps of the oxidation process of amino acid methionine (Met, CAS 63-68-3) by •OH radicals, leading to Met-OH• adduct and then to Met radical cation, were investigated theoretically over the last few years considering the aqueous environment as a continuum. In this work, following the same procedure that we used for the oxidation of dimethyl sulfide as reported by Domin et al. (J Phys Chem B, 121:9321), discrete water molecules, as well as relative positions, of the •OH radical to Met were taken from molecular dynamics calculations. The presence of water molecules strongly modifies the relative energies of Met-OH adducts and cations when water is properly modeled. Depending on the terminal functional groups and on the position of the •OH radical, several stable structures were found; however, the most stable radical is the N-centered or the S∴N radical cation. QTAIM analysis and valence bond (VB) treatment allowed for the characterization of the 2c∴3e nature of S∴N and S∴OH bonds. VB analysis estimated the probability of the heterolytic rupture of the •OH adduct that is modified by the presence of water molecules.

Structures and stabilities of glycine and water complexes

Structural elucidation, stability, properties and proton transfer processes of neutral and zwitterionic Gly(H2O)1-6 complexes are studied by ab initio calculations. Polarizable continuum model (PCM) is important for energy examination since solvent effects is sensitive to the energy. Glycine is fully solvated by five discrete water molecules under polarizable continuum model (PCM). The structure of neutral and zwitterionic Gly(H2O)1-6 complexes changes from a ring motif to a chain motif, and then to a cubic motif. The binding energy for neutral and zwitterionic Gly(H2O)1-6 complexes increases linearly as function of the number of water molecules increase, indicating Gly(H2O)1-6 complexes exhibit relatively higher stability. However, distortion of water molecules will cost more energy, leading to reduced binding energy per water molecule. The reduction is mainly attributed to the directivity and saturability of H-bonds. Importantly, we find the deprotonation of –NH2 for zwitterionic Gly(H2O)2-4 needs ~10 kcal/mol, which is consistent with the experiments.

Water molecules mediate zinc mobility in the bacterial zinc diffusion channel ZIPB

Regulated ion diffusion across biological membranes is vital for cell function. In a nanoscale ion channel, the active role of discrete water molecules in modulating hydrodynamic behaviors of individual ions is poorly understood because of the technical challenge of tracking water molecules through the channel. Here we report the results of a hydroxyl radical footprinting analysis of the zinc-selective channel ZIPB from the Gram-negative bacterium, Bordetella bronchiseptica Irradiating ZIPB by microsecond X-ray pulses activated water molecules to form covalent hydroxyl radical adducts at nearby residues, which were identified by bottom-up proteomics to detect residues that interact either with zinc or water in response to zinc binding. We found a series of residues exhibiting reciprocal changes in water accessibility attributed to alternating zinc and water binding. Mapping these residues to the previously reported crystal structure of ZIPB, we identified a water-reactive pathway that superimposed on a zinc translocation pathway consisting of two binuclear metal centers and an interim zinc-binding site. The cotranslocation of zinc and water suggested that pore-lining residues undergo a mode switch between zinc coordination and water binding to confer zinc mobility. The unprecedented details of water-mediated zinc transport identified here highlight an essential role of solvated waters in driving zinc coordination dynamics and transmembrane crossing.

Photoacidity of the 7-Hydroxyflavylium Cation.

Theoretical descriptions of excited state proton transfer (ESPT) have had various degrees of success. This work presents a theoretical description of the photodissociation of the 7-hydroxyflavylium cation (7-HF), the fundamental chromophoric moiety of anthocyanin natural plant pigments. ESPT of 7-HF is promoted by a significant shift of charge away from the OH group in the first singlet excited state, leading smoothly to the excited conjugate base and a protonated water cluster. Several factors contribute to the consistency of the results of the present study: (1) the theoretical approach (TD-DFT with the B3-LYP functional and def2-TZVP basis set utilizing Grimme's D3 dispersion correction); (2) the modeling of the solvent effect combining hydrogen bonding of the photoacid to a cluster of discrete water molecules in a water-like continuum solvent (COSMO); (3) the large S1 -S2 energy gap of flavylium cations; and (4) the electrostatics of the ESPT in which a proton is transferred from a cationic photoacid to water without Coulombic interaction between the proton and the conjugate base.

RNA as a Complex Polymer with Coupled Dynamics of Ions and Water in the Outer Solvation Sphere.

We unravel the internal and collective modes of a widely studied 58-nucleotide rRNA fragment in solvent using atomically detailed molecular dynamics simulations. The variation of lifetimes for water hydrogen bonds with nucleotide groups indicates heterogeneity of water dynamics on the RNA surface. The time scales of interactions of the discrete water molecules with RNA nucleotides extend from several hundred picoseconds to a few nanoseconds. We determine all of the association sites and the spatial distribution of residence times for Mg2+, K+, and water molecules in those sites. We provide insights into the population of Mg2+ and K+ ions and water molecules in the outer sphere and how their fluctuations are intricately linked with the kinetics of the 58-mer. We find that many of the long-lived Mg2+ sites identified from the simulations agree with the locations of ions in the X-ray structure. We determine the excess ion atmosphere around the rRNA and compare it with experimental data. We investigate the collective behavior of RNA, ions, and water, by performing a joint principle component analysis for the Cartesian coordinates of the RNA phosphorus atoms and for the occupation counts of the association sites. Our results indicate that the 58-mer system is a complex polymer, composed of RNA that is encased by a fluctuating network of associated counterions, co-ions, and water.

Influence of Water on the Oxidation of Dimethyl Sulfide by the ·OH Radical.

Oxidative stress of sulfur-containing biological molecules in aqueous environments may lead to the formation of adduct intermediates that are too short-lived to be experimentally detectable. In this study we have modeled the simplest of such oxidative reactions: the attack of dimethyl sulfide (DMS) by a hydroxyl radical (·OH) to form a radical adduct, whose subsequent heterolytic dissociation leads to a radical cation (DMS+) that is important for further reactions. We have modeled the aqueous environment with a limited number of discrete water molecules, selected after an original multistep procedure, and further embedded in a polarizable continuum model, to observe the impact of the water configuration on the heterolytic dissociation of the radical adduct. Molecular dynamics and quantum chemical methods (DFT, MP2, and CCSD) were used to elucidate the lowest energy structures resulting from the ·OH attack on DMS. Subsequent high level ab initio valence bond (BOVB) calculations revealed the possibility for the occurrence of subsequent heterolytic dissociation.

Understanding the influence of external perturbation on aziridinium ion formation

ABSTRACT A density functional theory study is performed to understand the effect of discrete water molecules during Az+ ion formation in nitrogen mustards. A comparative study in gas phase, and implicit and explicit solvation models of three drug molecules (mustine, chlorambucil and melphalan) is reported. Noteworthy changes in the structure and C–N stretching frequencies of the transition states have been observed in the presence of explicit water molecules. Presence of explicit water molecules reduces the positive charge around the tricyclic Az+ ring, and hence stabilising it. Both activation energy and rate constants are seen to be significantly affected in the presence of discrete water molecules.

"Solvent hydrogen-bond occlusion": A new model of polar desolvation for biomolecular energetics.

Water engages in two important types of interactions near biomolecules: it forms ordered "cages" around exposed hydrophobic regions, and it participates in hydrogen bonds with surface polar groups. Both types of interaction are critical to biomolecular structure and function, but explicitly including an appropriate number of solvent molecules makes many applications computationally intractable. A number of implicit solvent models have been developed to address this problem, many of which treat these two solvation effects separately. Here, we describe a new model to capture polar solvation effects, called SHO ("solvent hydrogen-bond occlusion"); our model aims to directly evaluate the energetic penalty associated with displacing discrete first-shell water molecules near each solute polar group. We have incorporated SHO into the Rosetta energy function, and find that scoring protein structures with SHO provides superior performance in loop modeling, virtual screening, and protein structure prediction benchmarks. These improvements stem from the fact that SHO accurately identifies and penalizes polar groups that do not participate in hydrogen bonds, either with solvent or with other solute atoms ("unsatisfied" polar groups). We expect that in future, SHO will enable higher-resolution predictions for a variety of molecular modeling applications. © 2017 Wiley Periodicals, Inc.

Structural and Functional Studies of a Newly Grouped Haloquadratum walsbyi Bacteriorhodopsin Reveal the Acid-resistant Light-driven Proton Pumping Activity

Retinal bound light-driven proton pumps are widespread in eukaryotic and prokaryotic organisms. Among these pumps, bacteriorhodopsin (BR) proteins cooperate with ATP synthase to convert captured solar energy into a biologically consumable form, ATP. In an acidic environment or when pumped-out protons accumulate in the extracellular region, the maximum absorbance of BR proteins shifts markedly to the longer wavelengths. These conditions affect the light-driven proton pumping functional exertion as well. In this study, wild-type crystal structure of a BR with optical stability under wide pH range from a square halophilic archaeon, Haloquadratum walsbyi (HwBR), was solved in two crystal forms. One crystal form, refined to 1.85 Å resolution, contains a trimer in the asymmetric unit, whereas another contains an antiparallel dimer was refined at 2.58 Å. HwBR could not be classified into any existing subgroup of archaeal BR proteins based on the protein sequence phylogenetic tree, and it showed unique absorption spectral stability when exposed to low pH values. All structures showed a unique hydrogen-bonding network between Arg(82) and Thr(201), linking the BC and FG loops to shield the retinal-binding pocket in the interior from the extracellular environment. This result was supported by R82E mutation that attenuated the optical stability. The negatively charged cytoplasmic side and the Arg(82)-Thr(201) hydrogen bond may play an important role in the proton translocation trend in HwBR under acidic conditions. Our findings have unveiled a strategy adopted by BR proteins to solidify their defenses against unfavorable environments and maintain their optical properties associated with proton pumping.

Structure and reactivity of phosphate diesters. Dependence on the nonleaving group

The hydrolytic reactivity of simple phosphate diesters with very good leaving groups is known to be practically independent of the nonleaving group at 100 °C. Calculations on the (too slow to measure) hydrolysis at 25 °C of a series of p-nitrophenyl diesters ROPO2––OpNP with a wide range of nonleaving group OR indicate a small but significant effect at the lower temperature, making the R = methyl ester the most reactive. This is in the opposite sense to the much larger effect observed for the reactions of triesters and consistent with a reaction driven primarily by leaving group departure. The calculations use a continuum model with up to four discrete water molecules: two or three waters give the best results.

Molecular simulations with solvent competition quantify water displaceability and provide accurate interaction maps of protein binding sites.

Binding sites present well-defined interaction patterns that putative ligands must meet. Knowing them is essential to guide structure-based drug discovery projects. However, complex aspects of molecular recognition-such as protein flexibility or the effect of aqueous solvation-hinder accurate predictions. This is particularly true for polar contacts, which are heavily influenced by the local environment and the behavior of discrete water molecules. Here we present and validate MDmix (Molecular Dynamics simulations with mixed solvents) as a method that provides much more accurate interaction maps than ordinary potentials (e.g., GRID). Additionally, MDmix also affords water displaceability predictions, with advantages over methods that use pure water as solvent (e.g., inhomogeneous fluid solvation theory). With current MD software and hardware solutions, predictions can be obtained in a matter of hours and visualized in a very intuitive manner. Thus, MDmix is an ideal complement in everyday structure-based drug discovery projects.

Bis{2-[(pyridin-2-yl)methyl-idene-amino]-benzoato-κ(3) N,N',O}chromium(III) nitrate monohydrate.

The title complex salt hydrate, [Cr(C13H9N2O2)2]NO3·H2O, comprises discrete cations, nitrate anions and solvent water mol­ecules. The CrIII atom is octa­hedrally coordinated by two anionic Schiff base ligands with the O atoms being cis. The two ligands differ significantly with dihedral angles between the pyridine and benzene rings of 4.8 (2) and 24.9 (2)°. The nitrate anion and solvent water mol­ecule were modelled as being disordered, with the major components having site-occupancy values of 0.856 (14) and 0.727 (16), respectively. The crystal is built of alternating layers of cations and of anions plus water mol­ecules, stacked along the c axis.

π- vs σ-Radical States of One-Electron-Oxidized DNA/RNA Bases: A Density Functional Theory Study

As a result of their inherent planarity, DNA base radicals generated by one-electron oxidation/reduction or bond cleavage form π- or σ-radicals. While most DNA base systems form π-radicals, there are a number of nucleobase analogues such as one-electron-oxidized 6-azauraci1, 6-azacytosine, and 2-thiothymine or one-electron reduced 5-bromouracil that form more reactive σ-radicals. Elucidating the availability of these states within DNA, base radical electronic structure is important to the understanding of the reactivity of DNA base radicals in different environments. In this work, we address this question by the calculation of the relative energies of π- and σ-radical states in DNA/RNA bases and their analogues. We used density functional theory B3LYP/6-31++G** method to optimize the geometries of π- and σ-radicals in Cs symmetry (i.e., planar) in the gas phase and in solution using the polarized continuum model (PCM). The calculations predict that σ- and π-radical states in one-electron-oxidized bases of thymine, T(N3-H)(•), and uracil, U(N3-H)(•), are very close in energy; i.e., the π-radical is only ca. 4 kcal/mol more stable than the σ-radical. For the one-electron-oxidized radicals of cytosine, C(•+), C(N4-H)(•), adenine, A(•+), A(N6-H)(•), and guanine, G(•+), G(N2-H)(•), G(N1-H)(•), the π-radicals are ca. 16-41 kcal/mol more stable than their corresponding σ-radicals. Inclusion of solvent (PCM) is found to stabilize the π- over σ-radical of each of the systems. U(N3-H)(•) with three discrete water molecules in the gas phase is found to form a three-electron σ bond between the N3 atom of uracil and the O atom of a water molecule, but on inclusion of full solvation and discrete hydration, the π-radical remains most stable.

Conformational preferences of taurine in the gas phase and in water

All feasible local minima of the neutral taurine (2-aminoethanesulfonic acid) in the gas phase and its zwitterionic form in water are explored using a density functional (M06-2X) that provides an accurate treatment of medium-range correlation energy and the recently improved solvation model SMD with the larger basis set (cc-pVTZ). In the gas phase, the conformer gtGg (II1) with the gauche− conformation around the NCH2CH2S sequence and the hydrogen bond between the sulfonic OH and the amine NH2 is found to be most preferred, which can be ascribed to the favored hyperconjugative n→σ* interaction between the lone electron pair of the amine nitrogen and the antibonding OH orbital of the sulfonic moiety. The calculated rotational constants of the conformer gtGg are consistent with the values obtained from LA-MB-FTMW experiments. In addition, the feasible structures of taurine±·(H2O)n complexes with a small number of water molecules (n=0, 1, 2, and 4) were investigated in the implicit SMD aqueous medium. The calculated results of taurine± with four water molecules support that taurine exists as a mixture of gauche and trans conformers in aqueous solution. Its gauche population is calculated to be 71%, which is in good agreement with the observed value of 67% from 1H NMR experiments in D2O. It is known that the increased population of the trans conformer for the taurine±·(H2O)4 complex is ascribed to the preferred solvation by the interactions between the solute and the discrete water molecules in the complex and by the polarization of the continuum water due to the complex.

Structural and vibrational study on zwitterions of l-threonine in aqueous phase using the FT-Raman and SCRF calculations

Quantum mechanical/molecular mechanics (QM/MM) calculations were performed to study the most stable theoretical structure of l-threonine in an aqueous solution phase and to observe the changes occurring in the structural and vibrational properties of l-threonine in the aqueous media. l-threonine was characterized by Raman spectroscopies in the solid state and in aqueous solution. Optimized geometries and relative stabilities for the monomer and two dimers were calculated using the hybrid B3LYP level taking into account the solvent effects by means of the integral equation formalism of the polarizable continuum model (IEF-PCM). The obtained results in the aqueous solution were compared with those calculated for the monomer in the gas phase. The presence of hydrogen bonding in the monomer of l-threonine was studied by means of the Atoms in Molecules theory (AIM) and natural bond orbital (NBO) studies. The complete assignments of the vibrational spectra of l-threonine in the aqueous solution was performed by using the Pulay’s scaled quantum mechanical force field (SQMFF) methodology. Additionaly, hydrated complexes of the monomer considering the interaction with one, two, three and four discrete water molecules were also studied taking into account the solvent effect by using the IEFPCM method. An agreement between theoretical and available experimental results was found.

Investigation of ionization equilibria of L-aspartic and L-glutamic acids in water at a microscopic level by DFT method

The pKa values of different dissociable groups of L-Aspartic and L-Glutamic acids in vacuo and in aqueous medium over a wide pH range have been estimated by DFT/B3LYP/6-31G(d) and 6-31G++(d,p) methods. For both the amino acids discrete water molecules (n = 0, 3 and 6) have been used to get the first hydration sphere. Starting from a low pH, all possible tautomers resulting from each dissociation step are assumed to exist in a cyclic equilibrium. The structures of the species involved in the dissociation and tautomerization processes have been optimized in vacuo and also in aqueous medium considering H-bonded water molecules under the PCM formalism. For obtaining pKa in aqueous medium the difference in Gibbs energy of the clusters H3O+.mH2O and (H2O) m+1 (m = an integer) is necessary and has been evaluated from computed literature data. Calculations reveal that in vacuo the neutral or less charged species predominate but in aqueous medium the zwitterionic or more chargeable forms contribute appreciably. The Gibbs energy changes for the microscopic cyclic equilibria have been estimated theoretically. These lead to overall (macroscopic) pKa values for the ionization steps which are in good agreement with available experimental data for both the amino acids.

Theoretical Study of the Importance of the Spectator Groups on the Hydrolysis of Phosphate Triesters

The spontaneous hydrolysis of a series of five triaryl and two dialkyl aryl phosphate triesters, previously studied experimentally, is examined theoretically using two different hybrid density functional methods, B3LYP and M06; two basic sets, 6-31+G(d) and 6-311++G(d,p); and the Gaussian 09 program. The B3LYP/6-31+G(d) methodology combined excellent accuracy with minor computational cost. The calculations show excellent quantitative agreement with experiment, which is best in the presence of three discrete water molecules. The results support a two-step mechanism involving a pentacovalent addition intermediate, with a lifetime of tenths of a millisecond. The rate-determining formation of this intermediate involves general base catalysis, defined by concerted proton transfers in a six-membered cyclic activated complex (TS1), which involves two hydrogen-bonded water molecules supporting a well-developed H(2)O···P bond (mean % evolution 77.83 ± 0.97). The third water molecule is hydrogen-bonded to P═O and subsequently involved in product formation via TS2. The effects on reactivity of all the groups attached to phosphorus in TS1 are examined in detail: the two non-leaving groups in particular are found to play an important role, accounting for the substantial difference in reactivity between triaryl and dialkyl aryl phosphate triesters.