Continuum Solvation Calculations Research Articles

Design, construction and in vivo functional assessment of a hinge truncated sFLT01.

Gene therapy for the treatment of ocular neovascularization has reached clinical trial phases. The AAV2-sFLT01 construct was already evaluated in a phase 1 open-label trial administered intravitreally to patients with advanced neovascular age-related macular degeneration. SFLT01 protein functions by binding to VEGF and PlGF molecules and inhibiting their activities simultaneously. It consists of human VEGFR1/Flt-1 (hVEGFR1), a polyglycine linker, and the Fc region of human IgG1. The IgG1 upper hinge region of the sFLT01 molecule makes it vulnerable to radical attacks and prone to causing immune reactions. This study pursued two goals: (i) minimizing the immunogenicity and vulnerability of the molecule by designing a truncated molecule called htsFLT01 (hinge truncated sFLT01) that lacked the IgG1 upper hinge and lacked 2 amino acids from the core hinge region; and (ii) investigating the structural and functional properties of the aforesaid chimeric molecule at different levels (in silico, in vitro, and in vivo). Molecular dynamics simulations and molecular mechanics energies combined with Poisson-Boltzmann and surface area continuum solvation calculations revealed comparable free energy of binding and binding affinity for sFLT01 and htsFLT01 to their cognate ligands. Conditioned media from human retinal pigment epithelial (hRPE) cells that expressed htsFLT01 significantly reduced tube formation in HUVECs. The AAV2-htsFLT01 virus suppressed vascular development in the eyes of newborn mice. The htsFLT01 gene construct is a novel anti-angiogenic tool with promising improvements compared to existing treatments.

Assessing the Performance of Mixed Strategies To Combine Lipophilic Molecular Similarity and Docking in Virtual Screening.

The accuracy of structure-based (SB) virtual screening (VS) is heavily affected by the scoring function used to rank a library of screened compounds. Even in cases where the docked pose agrees with the experimental binding mode of the ligand, the limitations of current scoring functions may lead to sensible inaccuracies in the ability to discriminate between actives and inactives. In this context, the combination of SB and ligand-based (LB) molecular similarity may be a promising strategy to increase the hit rates in VS. This study explores different strategies that aim to exploit the synergy between LB and SB methods in order to mitigate the limitations of these techniques, and to enhance the performance of VS studies by means of a balanced combination between docking scores and three-dimensional (3D) similarity. Particularly, attention is focused to the use of measurements of molecular similarity with PharmScreen, which exploits the 3D distribution of atomic lipophilicity determined from quantum mechanical-based continuum solvation calculations performed with the MST model, in conjunction with three docking programs: Glide, rDock, and GOLD. Different strategies have been explored to combine the information provided by docking and similarity measurements for re-ranking the screened ligands. For a benchmarking of 44 datasets, including 41 targets, the hybrid methods increase the identification of active compounds, according to the early (ROCe%) and total (AUC) enrichment metrics of VS, compared to pure LB and SB methods. Finally, the hybrid approaches are also more effective in enhancing the chemical diversity of active compounds. The datasets employed in this work are available in https://github.com/Pharmacelera/Molecular-Similarity-and-Docking.

Prediction of the n-octanol/water partition coefficients in the SAMPL6 blind challenge from MST continuum solvation calculations.

The IEFPCM/MST continuum solvation model is used for the blind prediction of n-octanol/water partition of a set of 11 fragment-like small moleculeswithin the SAMPL6 Part II Partition Coefficient Challenge. The partition coefficient of the neutral species (log P) was determined using an extended parametrization of the B3LYP/6-31G(d) version of the Miertus-Scrocco-Tomasi continuum solvation model in n-octanol. Comparison with the experimental data provided for partition coefficients yielded a root-mean square error (rmse) of 0.78 (log P units), which agrees with the accuracy reported for our method (rmse = 0.80) for nitrogen-containing heterocyclic compounds. Out of the 91 sets of log P values submitted by the participants, our submission is within those with an rmse < 1 and among the four best ranked physical methods. The largest errors involve three compounds: two with the largest positive deviations (SM13 and SM08), and one with the largest negative deviations (SM15). Here we report the potentiometric determination of the log P for SM13, leading to a value of 3.62 ± 0.02, which is in better agreement with most empirical predictions than the experimental value reported in SAMPL6. In addition, further inclusion of several conformations for SM08 significantly improved our results. Inclusion of these refinements led to an overall error of 0.51 (log P units),which supports the reliability of the IEFPCM/MST model for predicting the partitioning of neutral compounds.

Development of a Structure-Based, pH-Dependent Lipophilicity Scale of Amino Acids from Continuum Solvation Calculations.

Lipophilicity is a fundamental property to characterize the structure and function of proteins, motivating the development of lipophilicity scales. We report a versatile strategy to derive a pH-adapted scale that relies on theoretical estimates of distribution coefficients from conformational ensembles of amino acids. This is accomplished by using an accurately parametrized version of the IEFPCM/MST continuum solvation model as an effective way to describe the partitioning between n-octanol and water, in conjunction with a formalism that combines partition coefficients of neutral and ionic species of residues and the corresponding p Ka values of ionizable groups. Two weighting schemes are considered to derive solvent-like and protein-like scales, which have been calibrated by comparison with other experimental scales developed in different chemical/biological environments and pH conditions as well as by examining properties such as the retention time of small peptides and the recognition of antigenic peptides. A straightforward extension to nonstandard residues is enabled by this efficient methodological strategy.

A refined cavity construction algorithm for the conductor-like screening model.

A cavity construction algorithm based on the triangulation of an iso-surface is introduced as a new standard for dielectric continuum solvation calculations with the Conductor-like Screening Model COSMO. It overcomes deficiencies which have become apparent for the original COSMO standard cavity, especially in concave regions of the molecular shaped cavity. The new standard, called FINE Cavity, is described in this article with several application examples. The earlier COSMO cavity construction algorithms are described for comparison. © 2018 Wiley Periodicals, Inc.

Atomic Radius and Charge Parameter Uncertainty in Biomolecular Solvation Energy Calculations.

Atomic radii and charges are two major parameters used in implicit solvent electrostatics and energy calculations. The optimization problem for charges and radii is underdetermined, leading to uncertainty in the values of these parameters and in the results of solvation energy calculations using these parameters. This paper presents a new method for quantifying this uncertainty in implicit solvation calculations of small molecules using surrogate models based on generalized polynomial chaos (gPC) expansions. There are relatively few atom types used to specify radii parameters in implicit solvation calculations; therefore, surrogate models for these low-dimensional spaces could be constructed using least-squares fitting. However, there are many more types of atomic charges; therefore, construction of surrogate models for the charge parameter space requires compressed sensing combined with an iterative rotation method to enhance problem sparsity. We demonstrate the application of the method by presenting results for the uncertainties in small molecule solvation energies based on these approaches. The method presented in this paper is a promising approach for efficiently quantifying uncertainty in a wide range of force field parametrization problems, including those beyond continuum solvation calculations. The intent of this study is to provide a way for developers of implicit solvent model parameter sets to understand the sensitivity of their target properties (solvation energy) on underlying choices for solute radius and charge parameters.

Quantum mechanics models of the methanol dimer: O[sbnd]H⋯O hydrogen bonds of β-d-glucose moieties from crystallographic data

The interaction of two methanol molecules, simplified models of carbohydrates and cellulose, was examined using a variety of quantum mechanics (QM) levels of theory. Energy plots for hydrogen bonding distance (H⋯O) and angle (OH⋯O) were constructed. All but two experimental structures were located in stabilized areas on the vacuum phase energy plots. Each of the 399 models was analyzed with Bader's atoms-in-molecules (AIM) theory, which showed a widespread ability by the dimer models to form OH⋯O hydrogen bonds that have bond paths and Bond Critical Points. Continuum solvation calculations suggest that a portion of the energy-stabilized structures could occur in the presence of water. A survey of the Cambridge Structural Database (CSD) for all donor-acceptor interactions in β-D-glucose moieties examined the similarities and differences among the hydroxyl groups and acetal oxygen atoms that participate in hydrogen bonds. Comparable behavior was observed for the O2H, O3H, O4H, and O6H hydroxyls, acting either as acceptors or donors. Ring O atoms showed distinct hydrogen bonding behavior that favored mid-length hydrogen bonds.

Application of the quantum mechanical IEF/PCM-MST hydrophobic descriptors to selectivity in ligand binding.

We have recently reported the development and validation of quantum mechanical (QM)-based hydrophobic descriptors derived from the parametrized IEF/PCM-MST continuum solvation model for 3D-QSAR studies within the framework of the Hydrophobic Pharmacophore (HyPhar) method. In this study we explore the applicability of these descriptors to the analysis of selectivity fields. To this end, we have examined a series of 88 compounds with inhibitory activities against thrombin, trypsin and factor Xa, and the HyPhar results have been compared with 3D-QSAR models reported in the literature. The quantitative models obtained by combining the electrostatic and non-electrostatic components of the octanol/water partition coefficient yield results that compare well with the predictive potential of standard CoMFA and CoMSIA techniques. The results also highlight the potential of HyPhar descriptors to discriminate the selectivity of the compounds against thrombin, trypsin, and factor Xa. Moreover, the graphical representation of the hydrophobic maps provides a direct linkage with the pattern of interactions found in crystallographic structures. Overall, the results support the usefulness of the QM/MST-based hydrophobic descriptors as a complementary approach for disclosing structure-activity relationships in drug design and for gaining insight into the molecular determinants of ligand selectivity. Graphical Abstract Quantum Mechanical continuum solvation calculations performed with the IEF/PCM-MST method are used to derived atomic hydrophobic descriptors, which are then used to discriminate the selectivity of ligands against thrombin, trypsin and factor Xa. The descriptors provide complementary view to standard 3D-QSAR analysis, leading to a more comprehensive understanding of ligand recognition.

Thermochemical Factors Affecting the Dehalogenation of Aromatics

Halogenated aromatics are one of the largest chemical classes of environmental contaminants, and dehalogenation remains one of the most important processes by which these compounds are degraded and detoxified. The thermodynamic constraints of aromatic dehalogenation reactions are thus important for understanding the feasibility of such reactions and the redox conditions necessary for promoting them. Accordingly, the thermochemical properties of the (poly)fluoro-, (poly)chloro-, and (poly)bromobenzenes, including standard enthalpies of formation, bond dissociation enthalpies, free energies of reaction, and the redox potentials of Ar-X/Ar-H couples, were investigated using a validated density functional protocol combined with continuum solvation calculations when appropriate. The results highlight the fact that fluorinated aromatics stand distinct from their chloro- and bromo- counterparts in terms of both their relative thermodynamic stability toward dehalogenation and how different substitution patterns give rise to relevant properties, such as bond strengths and reduction potentials.

Structural Modeling of HCV NS3/4A Serine Protease Drug-Resistance Mutations Using End-Point Continuum Solvation and Side-Chain Flexibility Calculations

Computational methods of modeling protein-ligand interactions have gained widespread application in modern drug discovery. In continuum solvation-based methods of binding affinity estimation, limited description of solvent environment and protein flexibility is traded for a time scale that fits medicinal chemistry test cycles. The results of this speed-accuracy trade-off have been promising in terms of modeling structure-activity relationships of ligand series against protein targets. The potential of these approaches in recapitulating structural and energetic effects of resistance mutations, which involve large changes in binding affinity, remains relatively unexplored. We used continuum solvation binding affinity predictions and graph theory-based flexibility calculations to model thirteen drug resistance mutations in HCV NS3/4A serine protease, against three small-molecule inhibitors, with a 2-fold objective: quantitative assessment of binding energy predictions against experimental data and elucidation of structural/energetic determinants of resistance. The results show statistically significant correlation between predicted and experimental binding affinities, with R(2) and predictive index of up to 0.83 and 0.91, respectively. The level of accuracy was consistent with what has been reported for the inverse problem of binding affinity estimation of congeneric ligands against the same target. The quality of predictions was poor for mutations involving induced-fit effects, primarily, because of the lack of entropy terms. Flexibility analysis explained this discrepancy by indicating characteristic changes in side-chain mobility of a key binding site residue. The combined results from two approaches provide novel insights regarding the molecular mechanism of resistance. NS3/4A inhibitors, with large P2 substituents, derive high affinity with optimal van der Waals interactions in the S2 subsite, in order to overcome unfavorable desolvation and entropic cost of induced-fit effects. High-level resistance mutations tend to increase the desolvation and/or entropic barrier to ligand binding. The lead optimization strategies should, therefore, address the balance of these opposing energetic contributions in both the wild-type and mutant target.

A reliable and efficient first principles‐based method for predicting pKa values. III. Adding explicit water molecules: Can the theoretical slope be reproduced and pKa values predicted more accurately?

A popular method for predicting pK(a) values for organic molecules in aqueous solution is to establish empirical linear least-squares fits between calculated deprotonation energies and known experimental pK(a) values. In virtually all such calculations, the empirically observed slope of the pK(a) vs. ΔE fit is significantly less than the theoretical value, 1/(2.303RT) (which is 0.73 mol/kcal at room temperature). In our own continuum solvation calculations (Zhang et al., J Phys Chem A 2010, 114, 432), the empirical slope for carboxylic acids was only 0.23 mol/kcal, despite the excellent fit to the experimental pK(a) values. There has been much speculation about the reason for this phenomenon. Although the ΔE - pK(a) relation neglects entropic effects, these are expected to largely cancel. The most likely cause for the strange behavior of the fitted slope is explicit solute-solvent (water) interactions, especially involving the ions, which cannot be described accurately by continuum solvation models. We used our previously developed pK(a) protocol (OLYP/6-311+G(d,p)//3-21G(d) with the COSMO solvation model) to investigate the effect of adding one or two explicit water molecules to the system. The slopes for organic acids (especially carboxylic acids) are much closer to the theoretical value when explicit water molecules are added to both the neutral molecule and the anion. However, explicit water molecules have almost no effect on the slopes for organic bases. Adding explicit water molecules to the ions only produces intermediate results. Unfortunately, linear fits involving explicit water molecules have much larger errors than with continuum solvation models alone and are also much more expensive. Consequently, they are not suitable for large-scale pK(a) calculations. The results compared with literature values showed that our predicted pK(a) s are more accurate.

Molecular modeling of class I and II alleles of the major histocompatibility complex in Salmo salar

Knowledge of the 3D structure of the binding groove of major histocompatibility (MHC) molecules, which play a central role in the immune response, is crucial to shed light into the details of peptide recognition and polymorphism. This work reports molecular modeling studies aimed at providing 3D models for two class I and two class II MHC alleles from Salmo salar (Sasa), as the lack of experimental structures of fish MHC molecules represents a serious limitation to understand the specific preferences for peptide binding. The reliability of the structural models built up using bioinformatic tools was explored by means of molecular dynamics simulations of their complexes with representative peptides, and the energetics of the MHC-peptide interaction was determined by combining molecular mechanics interaction energies and implicit continuum solvation calculations. The structural models revealed the occurrence of notable differences in the nature of residues at specific positions in the binding groove not only between human and Sasa MHC proteins, but also between different Sasa alleles. Those differences lead to distinct trends in the structural features that mediate the binding of peptides to both class I and II MHC molecules, which are qualitatively reflected in the relative binding affinities. Overall, the structural models presented here are a valuable starting point to explore the interactions between MHC receptors and pathogen-specific interactions and to design vaccines against viral pathogens.

Explicitly representing the solvation shell in continuum solvent calculations.

A method is presented to explicitly represent the first solvation shell in continuum solvation calculations. Initial solvation shell geometries were generated with classical molecular dynamics simulations. Clusters consisting of solute and 5 solvent molecules were fully relaxed in quantum mechanical calculations. The free energy of solvation of the solute was calculated from the free energy of formation of the cluster, and the solvation free energy of the cluster was calculated with continuum solvation models. The method has been implemented with two continuum solvation models, a Poisson-Boltzmann model and the IEF-PCM model. Calculations were carried out for a set of 60 ionic species. Implemented with the Poisson-Boltzmann model the method gave an unsigned average error of 2.1 kcal/mol and a rmsd of 2.6 kcal/mol for anions; for cations the unsigned average error was 2.8 kcal/mol and the rmsd 3.9 kcal/mol. Similar results were obtained with the IEF-PCM model.

Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions

We present a new continuum solvation model based on the quantum mechanical charge density of a solute molecule interacting with a continuum description of the solvent. The model is called SMD, where the "D" stands for "density" to denote that the full solute electron density is used without defining partial atomic charges. "Continuum" denotes that the solvent is not represented explicitly but rather as a dielectric medium with surface tension at the solute-solvent boundary. SMD is a universal solvation model, where "universal" denotes its applicability to any charged or uncharged solute in any solvent or liquid medium for which a few key descriptors are known (in particular, dielectric constant, refractive index, bulk surface tension, and acidity and basicity parameters). The model separates the observable solvation free energy into two main components. The first component is the bulk electrostatic contribution arising from a self-consistent reaction field treatment that involves the solution of the nonhomogeneous Poisson equation for electrostatics in terms of the integral-equation-formalism polarizable continuum model (IEF-PCM). The cavities for the bulk electrostatic calculation are defined by superpositions of nuclear-centered spheres. The second component is called the cavity-dispersion-solvent-structure term and is the contribution arising from short-range interactions between the solute and solvent molecules in the first solvation shell. This contribution is a sum of terms that are proportional (with geometry-dependent proportionality constants called atomic surface tensions) to the solvent-accessible surface areas of the individual atoms of the solute. The SMD model has been parametrized with a training set of 2821 solvation data including 112 aqueous ionic solvation free energies, 220 solvation free energies for 166 ions in acetonitrile, methanol, and dimethyl sulfoxide, 2346 solvation free energies for 318 neutral solutes in 91 solvents (90 nonaqueous organic solvents and water), and 143 transfer free energies for 93 neutral solutes between water and 15 organic solvents. The elements present in the solutes are H, C, N, O, F, Si, P, S, Cl, and Br. The SMD model employs a single set of parameters (intrinsic atomic Coulomb radii and atomic surface tension coefficients) optimized over six electronic structure methods: M05-2X/MIDI!6D, M05-2X/6-31G, M05-2X/6-31+G, M05-2X/cc-pVTZ, B3LYP/6-31G, and HF/6-31G. Although the SMD model has been parametrized using the IEF-PCM protocol for bulk electrostatics, it may also be employed with other algorithms for solving the nonhomogeneous Poisson equation for continuum solvation calculations in which the solute is represented by its electron density in real space. This includes, for example, the conductor-like screening algorithm. With the 6-31G basis set, the SMD model achieves mean unsigned errors of 0.6-1.0 kcal/mol in the solvation free energies of tested neutrals and mean unsigned errors of 4 kcal/mol on average for ions with either Gaussian03 or GAMESS.

Solvation enthalpies of neutral solutes in water and octanol

The balance between electrostatic and non-electrostatic enthalpic contributions to the free energy of solvation of a series of neutral solutes in water and n-octanol is examined by means of continuum solvation calculations based on the Miertus–Scrocco–Tomasi (MST) method. The experimental data indicate that the solvation enthalpy of hydrocarbons is very similar in water and n-octanol, and that the enthalpic contribution measured for polar compounds is larger in water than in n-octanol. According to MST calculations, the different magnitude of the solvation enthalpy found for polar compounds in the two solvents can be largely attributed to the electrostatic contribution. Moreover, the results point out that there is close resemblance between the non-electrostatic components for both hydrocarbons and polar compounds in the two solvents. Finally, the results show the power of current continuum models like MST to dissect the total free energy of solvation in entropic and enthalpic contributions and suggest that new refinements of continuum solvation models should include not only the fitting to solvation free energies, but also their enthalpic components.

Optimized Parameters for Continuum Solvation Calculations with Carbohydrates

Continuum solvent models have been shown to be an efficient method for the calculation of the energetics of biomolecules in solution. However, for these methods to produce accurate results, an appropriate set of atomic radii or volumes is needed. While these have been developed for proteins and nucleic acids, the same is not true of carbohydrates. Here, a set of optimized parameters for continuum solvation calculations of carbohydrates in conjunction with the Carbohydrate Solution Force Field are presented. Explicit solvent free-energy perturbation simulations were performed on a set of hexapyranose sugars and used to fit atomic radii for Poisson-Boltzmann and generalized-Born calculations, and to fit atomic volumes for use with the analytical continuum electrostatics model. The solvation energetics computed with the optimized radii and a Poisson-Boltzmann model show remarkable agreement with explicit solvent simulation, with a root-mean-square error of 1.19 kcal/mol over a large test set of sugars in many conformations. The generalized-Born model gives slightly poorer agreement, but still correlates very strongly, with an error of 1.69 kcal/mol. The analytical continuum electrostatics model correlates well with the explicit solvent results, but gives a larger error of 4.71 kcal/mol. The remarkable agreement between the solvation free energies computed in explicit and implicit solvent provides strong motivation for the use of implicit solvent models in the simulation of carbohydrate-containing systems.

Validation of density functional modeling protocols on experimental bis(μ-oxo)/μ-η2:η2-peroxo dicopper equilibria

The bis(mu-oxo)/mu-eta(2):eta(2)-peroxo equilibria for seven supported Cu(2)O(2) cores were studied with different hybrid and nonhybrid density functional theory models, namely, BLYP, mPWPW, TPSS, TPSSh, B3LYP, mPW1PW, and MPW1K. Supporting ligands 3,3'-iminobis(N,N-dimethylpropylamine), N,N,N',N',N''-pentamethyldipropylenetriamine, N-[2-(pyridin-2-yl)ethyl]-N,N,N'-trimethylpropane-1,3-diamine, bis[2-(2-pyridin-2-yl)ethyl]methylamine, bis[2-(4-methoxy-2-pyridin-2-yl)ethyl]methylamine, bis[2-(4-N,N-dimethylamino-2-pyridin-2-yl)ethyl]methylamine, and 1,4,7-triisopropyl-1,4,7-triazacyclononane were chosen on the basis of the availability of experimental data for comparison. Density functionals were examined with respect to their ability accurately to reproduce experimental properties, including, in particular, geometries and relative energies for the bis(mu-oxo) and side-on peroxo forms. While geometries from both hybrid and nonhybrid functionals were in good agreement with experiment, the incorporation of Hartree-Fock (HF) exchange in hybrid density functionals was found to have a large, degrading effect on predicted relative isomer energies. Specifically, hybrid functionals predicted the mu-eta(2):eta(2)-peroxo isomer to be too stable by roughly 5-10 kcal mol(-1) for each 10% of HF exchange incorporated into the model. Continuum solvation calculations predict electrostatic effects to favor bis(mu-oxo) isomers by 1-4 kcal mol(-1) depending on ligand size, with larger ligands having smaller differential solvation effects. Analysis of computed molecular partition functions suggests that nonzero measured entropies of isomerization are likely to be primarily associated with interactions between molecular solutes and their first solvation shell.

&lt;b&gt;SOLVENT EFFECTS ON THE MAGNETIC SHIELDING OF TERTIARY BUTYL ALCOHOL, TERTIARY BUTYL AMINE AND RELATED MOLECULES&lt;/b&gt;

The magnetic shielding and its polarizabilities, have been calculated for tertiary butyl alcohol and tertiary butyl amine. These have been used to rationalise the solvent shifts of the proton spectra of the interesting cosolvent systems with water recently measured by Kipkemboi, et al. Continuum solvation calculations and calculations of Buckingham A and B for relevant nuclei are presented. New parameters relevant to the 13C, 15N and 17O NMR spectra in the same systems have been calculated. There is wider discussion of the validity of chemical shift estimation methods. New calculations on the related molecules Si(CH3)4 (TMS), neo-pentane C(CH3)4 and tetramethyl ammonium cation N(CH3)4(+) have also been presented. KEY WORDS: Solvent effects, Magnetic shielding, Tertiary butyl alcohol, Tertiary butyl amine, Continuum solvation calculations, Chemical shift estimation methods Bull. Chem. Soc. Ethiop. 2005, 19(2), 243-255.

Hydrogen bonding, solvation, and hydrolysis of cisplatin: a theoretical study.

Density functional calculations on a range of hydrogen bonded clusters of cisplatin are reported. A systematic search of 1:1 cisplatin:water complexes reveals only three stable minima, which contain a number of common, recurring interactions, such as an N-H...O-H...Cl bridging mode. Expanding these clusters by adding water molecules leads to a model of the first solvation shell of cisplatin, which contains the above motifs along with several strong water-water interactions. The strengths of such interactions are rationalized on the basis of electrostatic potentials, and quantified by use of Atoms in Molecules properties. This analysis also allows us to estimate cisplatin's position on Abraham's hydrogen bond acidity and basicity scales, indicating that cisplatin is a strong donor and acceptor of hydrogen bonds due to the dominance of hard, electrostatic interactions. The effects of this explicit solvation on the barrier to hydrolysis, and hence activation, of cisplatin are explored, indicating a slightly higher barrier than in the gas phase, leading to better agreement with experiment than either gas phase or continuum solvation calculations.

U-Shaped Donor [Bridge] Acceptor Systems with Remarkable Charge Transfer Fluorescent Properties: An Experimental and Computational Investigation

The photoinduced intramolecular electron transfer in two donor−bridge−acceptor systems was studied using (time-resolved) fluorescence and transient absorption techniques. DPN[8cy]DCV and DPMN[8cy]DCV consist of a 1,4-diphenylnaphthalene (DPN) and a 1,4-diphenyl-5,8-dimethoxynaphthalene (DPMN) electron donor, respectively, and the 1,1-dicyanovinyl acceptor (DCV) in both systems. The overall geometry of the saturated hydrocarbon bridge is U-shaped, separating the donor and acceptor by an 8-σ-bond through-bond distance and a 5.8 Å (center-to-center) through-space distance in the ground state. In all solvents fast electron transfer is observed in both systems resulting in a fluorescent charge transfer (CT) state. Especially for DPN[8cy]DCV CT fluorescence can be detected over a wide range of solvent polarity. The solvent dependence of the CT fluorescence position, lifetime, and quantum yield could thus be employed to estimate the solvent effect on the dipole moment of the CT state, the rate of charge recombination, and the electronic coupling (V) between donor and acceptor. It is concluded that in the (luminescent) CT state both the distance between donor and acceptor and their electronic coupling are virtually solvent independent, which excludes a solvent-mediated electron-transfer pathway. Gas phase (U)HF ab initio MO calculations carried out on the model molecule DMN[8cy]DCV (which contains a computationally less demanding 1,4-dimethoxynaphthalene donor) predict that the center-to-center distance between the two chromophores in the CT state is about 4.4 Å which amounts to a 1.4 Å contraction with respect to the ground state geometry. The degree of contraction is almost entirely due to pyramidalization at the DCV radical anion site and occurs in the direction of the dimethoxynaphthalene radical cation for electrostatic reasons. The calculated weak out-of-plane bending potential associated with this pyramidalization implies that the degree and direction of pyramidalization in the CT state of the DCV moiety can be preserved in solution and that it is fairly insensitive toward solvent polarity as shown by the results of UHF/6-31G(d) continuum solvation calculations and as supported by the experimental results for DPN[8cy]DCV. The small and constant D/A separation in the CT state also explains the experimentally found constancy of the electronic coupling, which must be of a direct through-space (TS) nature because no solvent molecules can be accommodated between D and A. Remarkably, while the charge recombination in DPMN[8cy]DCV displays the strong rate enhancement with increasing solvent polarity typical for charge recombination occurring under “inverted region conditions”, the rate of charge recombination in DPN[8cy]DCV is virtually constant over a wide range of solvent polarities. This very unusual behavior appears to be related to the presence of parallel charge recombination pathways to respectively the ground state and to a local triplet state with an opposite solvent dependence of their rate.