Showing papers on "Solvation published in 2002"

Solvents and Solvent Effects in Organic Chemistry.

Abstract: INTRODUCTION SOLUTE-SOLVENT INTERACTIONS Solutions Intermolecular Forces Solvation Preferential Solvation Micellar Solvation (Solubilization) Ionization and Dissociation CLASSIFICATION OF SOLVENTS Classification of Solvents According to Chemical Constitution Classification of Solvents Using Physical Constants Classification of Solvents in Terms of Acid-Base Behaviour Classification of Solvents in Terms of Specific Solute/Solvent Interactions Classification of Solvents Using Multivariate Statistical Methods SOLVENT EFFECTS ON THE POSITION OF HOMOGENEOUS CHEMICAL EQUILIBRIA General Remarks Solvent Effects on Acid/Base Equilibria Solvent Effects on Tautomeric Equilibria Solvent Effects on other Equilibria SOLVENT EFFECTS ON THE RATES OF HOMOGENEOUS CHEMICAL REACTIONS General Remarks Gas-Phase Reactivities Qualitative Theory of Solvent Effects on Reaction Rates Quantitative Theories of Solvent Effects on Reaction Rates Specific Solvation Effects on Reaction Rates SOLVENT EFFECTS ON THE ABSORPTION SPECTRA OF ORGANIC COMPOUNDS General Remarks Solvent Effects on UV/Vis Spectra Solvent Effects on Infrared Spectra Solvent Effects on Electron Spin Resonance Spectra Solvent Effects on Nuclear Magnetic Resonance Spectra EMPIRICAL PARAMETERS OF SOLVENT POLARITY Linear Gibbs Energy Relationships Empirical Parameters of Solvent Polarity from Equilibrium Measurements Empirical Parameters of Solvent Polarity from Kinetic Measurements Empirical Parameters of Solvent Polarity from Spectroscopic Measurements Empirical Parameters of Solvent Polarity from Other Measurements Interrelation and Application of Solvent Polarity Parameters Multiparameter Approaches SOLVENTS AND GREEN CHEMISTRY Green Chemistry Reduction of Solvent Use Green Solvent Selection Non-Traditional Solvents Outlook APPENDIX: PROPERTIES, PURIFICATION, AND USE OF ORGANIC SOLVENTS Physical Properties Purification of Organic Solvents Spectroscopic Solvents Solvents as Reaction Media Solvents for Recrystallization Solvents for Extraction and Partitioning (Distribution) Solvents for Adsorption Chromatography Solvents for Acid/Base Titrations in Non-Aqueous Media Solvents for Electrochemistry Toxicity of Organic Solvents

Fast, efficient generation of high-quality atomic charges. AM1-BCC model: II. Parameterization and validation

Abstract: We present the first global parameterization and validation of a novel charge model, called AM1-BCC, which quickly and efficiently generates high-quality atomic charges for computer simulations of organic molecules in polar media. The goal of the charge model is to produce atomic charges that emulate the HF/6-31G* electrostatic potential (ESP) of a molecule. Underlying electronic structure features, including formal charge and electron delocalization, are first captured by AM1 population charges; simple additive bond charge corrections (BCCs) are then applied to these AM1 atomic charges to produce the AM1-BCC charges. The parameterization of BCCs was carried out by fitting to the HF/6-31G* ESP of a training set of >2700 molecules. Most organic functional groups and their combinations were sampled, as well as an extensive variety of cyclic and fused bicyclic heteroaryl systems. The resulting BCC parameters allow the AM1-BCC charging scheme to handle virtually all types of organic compounds listed in The Merck Index and the NCI Database. Validation of the model was done through comparisons of hydrogen-bonded dimer energies and relative free energies of solvation using AM1-BCC charges in conjunction with the 1994 Cornell et al. forcefield for AMBER.(13) Homo- and hetero-dimer hydrogen-bond energies of a diverse set of organic molecules were reproduced to within 0.95 kcal/mol RMS deviation from the ab initio values, and for DNA dimers the energies were within 0.9 kcal/mol RMS deviation from ab initio values. The calculated relative free energies of solvation for a diverse set of monofunctional isosteres were reproduced to within 0.69 kcal/mol of experiment. In all these validation tests, AMBER with the AM1-BCC charge model maintained a correlation coefficient above 0.96. Thus, the parameters presented here for use with the AM1-BCC method present a fast, accurate, and robust alternative to HF/6-31G* ESP-fit charges for general use with the AMBER force field in computer simulations involving organic small molecules.

New developments in the polarizable continuum model for quantum mechanical and classical calculations on molecules in solution

Abstract: The polarizable continuum model (PCM), used for the calculation of molecular energies, structures, and properties in liquid solution has been deeply revised, in order to extend its range of applications and to improve its accuracy. The main changes effect the definition of solute cavities, of solvation charges and of the PCM operator added to the molecular Hamiltonian, as well as the calculation of energy gradients, to be used in geometry optimizations. The procedure can be equally applied to quantum mechanical and to classical calculations; as shown also with a number of numerical tests, this PCM formulation is very efficient and reliable. It can also be applied to very large solutes, since all the bottlenecks have been eliminated to obtain a procedure whose time and memory requirements scale linearly with solute size. The present procedure can be used to compute solvent effects at a number of different levels of theory on almost all the chemical systems which can be studied in vacuo.

Characterizing ionic liquids on the basis of multiple solvation interactions.

Abstract: Room-temperature ionic liquids (RTILs) are useful in many chemical applications. Recent publications have attempted to determine the polarity of RTILs using empirical solvent polarity scales. The results have indicated that most RTILs have similar polarities. Nevertheless, RTILs are capable of behaving quite differently when used as solvents in organic synthesis, matrixes in matrix-assisted laser desorption/ionization (MALDI) mass spectrometry, liquid−liquid extraction, and as stationary phases in gas chromatography. The work presented in this study uses a linear free energy approach to characterize 17 RTILs on the basis of their distinct multiple solvation interactions with probe solute molecules. This model provides data that can be used to help identify the interactions and properties that are important for specific chemical applications.

Ions at the Air/Water Interface

Abstract: We present results from theoretical studies of aqueous ionic solvation of alkali halides aimed at developing a microscopic description of structure and dynamics at the interface between air and sal...

A Priori Phase Equilibrium Prediction from a Segment Contribution Solvation Model

Abstract: An activity coefficient model using molecular solvation based on the COSMO-RS method is proposed. In this model, quantum mechanical COSMO calculations are performed to obtain the screening charges for molecules in a perfect conductor. A statistical mechanical model that considers molecules to be a collection of surface segments is developed for the calculation of segment activity coefficients using these screening charges. Activity coefficients for molecules are then obtained by summing the contributions of the segments. This model requires only a single radius for each atom in the COSMO solvation calculations, one universal parameter to discern hydrogen-bond acceptors and donors, and two universal parameters to determine segment interactions. This is a significantly fewer number of parameters for phase equilibrium calculations than group contribution methods such as the UNIFAC (168 parameters) and modified UNIFAC (612 parameters) models. The resulting completely a priori prediction method results in abso...

How ions affect the structure of water.

Abstract: We model ion solvation in water We use the MB model of water, a simple two-dimensional statistical mechanical model in which waters are represented as Lennard-Jones disks having Gaussian hydrogen-bonding arms We introduce a charge dipole into MB waters We perform (NPT) Monte Carlo simulations to explore how water molecules are organized around ions and around nonpolar solutes in salt solutions The model gives good qualitative agreement with experiments, including Jones−Dole viscosity B coefficients, Samoilov and Hirata ion hydration activation energies, ion solvation thermodynamics, and Setschenow coefficients for Hofmeister series ions, which describe the salt concentration dependence of the solubilities of hydrophobic solutes The two main ideas captured here are (1) that charge densities govern the interactions of ions with water, and (2) that a balance of forces determines water structure: electrostatics (water's dipole interacting with ions) and hydrogen bonding (water interacting with neighbori

Biological water at the protein surface: dynamical solvation probed directly with femtosecond resolution.

Abstract: Biological water at the interface of proteins is critical to their equilibrium structures and enzyme function and to phenomena such as molecular recognition and protein-protein interactions. To actually probe the dynamics of water structure at the surface, we must examine the protein itself, without disrupting the native structure, and the ultrafast elementary processes of hydration. Here we report direct study, with femtosecond resolution, of the dynamics of hydration at the surface of the enzyme protein Subtilisin Carlsberg, whose single Trp residue (Trp-113) was used as an intrinsic biological fluorescent probe. For the protein, we observed two well separated dynamical solvation times, 0.8 ps and 38 ps, whereas in bulk water, we obtained 180 fs and 1.1 ps. We also studied a covalently bonded probe at a separation of approx 7 A and observed the near disappearance of the 38-ps component, with solvation being practically complete in (time constant) 1.5 ps. The degree of rigidity of the probe (anisotropy decay) and of the water environment (protein vs. micelle) was also studied. These results show that hydration at the surface is a dynamical process with two general types of trajectories, those that result from weak interactions with the selected surface site, giving rise to bulk-type solvation (approx 1 ps), and those that have a stronger interaction, enough to define a rigid water structure, with a solvation time of 38 ps, much slower than that of the bulk. At a distance of approx 7 A from the surface, essentially all trajectories are bulk-type. The theoretical framework for these observations is discussed.

Absolute pKa determinations for substituted phenols

Abstract: The CBS-QB3 method was used to calculate the gas-phase free energy difference between 20 phenols and their respective anions, and the CPCM continuum solvation method was applied to calculate the free energy differences of solvation for the phenols and their anions. The CPCM solvation calculations were performed on both gas-phase and solvent-phase optimized structures. Absolute pKa calculations with solvated phase optimized structures for the CPCM calculations yielded standard deviations and root-mean-square errors of less than 0.4 pKa unit. This study is the most accurate absolute determination of the pKa values of phenols, and is among the most accurate of any such calculations for any group of compounds. The ability to make accurate predictions of pKa values using a coherent, well-defined approach, without external approximations or fitting to experimental data, is of general importance to the chemical community. The solvated phase optimized structures of the anions are absolutely critical to obtain thi...

Biological water: femtosecond dynamics of macromolecular hydration

Abstract: The unique features of a macromolecule and water as a solvent make the issue of solvation unconventional, with questions about the static versus dynamic nature of hydration and the physics of orientational and translational diffusion at the boundary. For proteins, the hydration shell that covers the surface is critical to the stability of its structure and function. Dynamically speaking, the residence time of water at the surface is a signature of its mobility and binding. With femtosecond time resolution it is possible to unravel the shortest residence times which are key for the description of the hydration layer, static or dynamic. In this article we review these issues guided by experimental studies, from this laboratory, of polar hydration dynamics at the surfaces of two proteins (Subtilisin Carlsberg (SC) and Monellin). The natural probe tryptophan amino acid was used for the interrogation of the dynamics, and for direct comparison we also studied the behavior in bulk watera complete hydration in 1 ...

Novel generalized Born methods

Abstract: The generalized Born (GB) model is a simple continuum dielectric model for the calculation of molecular electrostatic solvation energies. It is a pairwise approximation to the solution of the Poisson equation for continuum electrostatic solvation. Key to the GB method is the calculation of Born radii for every atom in the system. We introduce two new methods for determining Born radii. The first is a two-parameter grid-based method that uses nearly the same molecular volume that is used in conventional Poisson calculations. The second is a five-parameter analytical method that utilizes a molecular volume built from a superposition of atomic functions. The analytical method, distinct from the grid-based algorithm, is amenable to force-based calculations, e.g., energy minimization and molecular dynamics. Unlike other Born radii methods, both algorithms employ a new empirically determined correction term that includes energetic effects beyond the Coulomb field approximation. With this correction term, the grid-based algorithm generally yields Born radii with greater than 0.99 correlation versus converged numerically derived Poisson Born radii. The analytical method reproduces Born radii with approximately 0.95 correlation versus Poisson-derived Born radii. With respect to absolute solvation energies, the grid-based method achieves an overall 1.3% error versus converged Poisson solutions for a set of 3029 single-chain proteins obtained from the Brookhaven Protein Data Bank. On the other hand, the analytic method delivers modest 2–4 % errors versus the Poisson solutions for the same data set. Results concerning absolute solvation energies of RNA and relative solvation energies in two sets of protein conformations are also presented.

Solvent Mixtures: Properties and Selective Solvation

Abstract: Introduction Properties of Binary Solvent Mixtures The Structure of Solvent Mixtures Preferential Solvation in Binary Solvent Mixtures Preferential Solvation of Solutes Multicomponent Solvent Mixtures Solvents and Solvent Mixture Index Subject Index

Novel Electrochemical Studies of Ionic Liquids

Abstract: Room-temperature ionic liquids (ILs) have been proposed as alternative solvents for organic synthesis, separations, and electrochemical applications. Here, we report studies that probe the electrochemical and solvation properties of a tetraalkylammonium (methyltributylammonium bis(trifluoromethylsulfon)imide, M3BNIm) and an imidazolium (1-butyl-3-methylimidazolium hexafluorophosphate, BMIPF6) based ionic liquid. It is demonstrated that despite impurities, the cathodic limit at a Pt electrode is enhanced for the tetraalkylammonium-based IL. Electrogenerated chemiluminescence of tris(2,2‘-bipyrindinyl)ruthenium (Ru(bpy)32+) was observed in both ionic liquids, and differences in the response were interpreted in terms of the solvent reactivity and polarity. As ILs have been proposed as alternatives to organic solvents in extraction processes, an understanding of the relative lipophilicity of the IL ions and the equilibrium potential difference established across the IL/water interface is of fundamental releva...

The hydrophobic effect and the influence of solute-solvent attractions

Abstract: We have studied the effect of weak solute−solvent attractions on the solvation of nonpolar molecules in water at ambient conditions using an extension and improved parameterization of the theory of solvation due to Lum, Chandler, and Weeks [J. Phys. Chem. B 1999, 103, 4570]. With a reasonable strength of alkane−water interactions, an accurate prediction of the alkane−water interfacial tension is obtained. As previously established for solutes with no attractive interactions with water, the free energy of solvation scales with volume for small solutes and with surface area for large solutes. The crossover to the latter regime occurs on a molecular length scale. It is associated with the formation of a liquid−vaporlike interface, a drying interface, between the large hydrophobic solute and liquid water. In the absence of attractions, this interface typically lies more than one solvent molecular diameter away from the hard sphere surface. With the addition of attractive interactions between water and the har...

Gram-scale synthesis of monodisperse gold colloids by the solvated metal atom dispersion method and digestive ripening and their organization into two- and three-dimensional structures.

Abstract: We describe a synthetic procedure for preparation of large quantities of monodisperse thiol-stabilized gold colloids in toluene solution. The method is based on the solvated metal atom dispersion technique (SMAD), which is very suitable for preparation of large amounts of metal colloidal solutions, as well as of metal sulfide, metal oxide, and other types of dispersed compounds in different solvents. A combination of two different solvents like acetone and toluene is used for the preparation of the gold colloids. The necessity of initially carrying out the SMAD reaction in acetone comes from its high degree of solvation of gold particles. Acetone acts as a preliminary stabilizing agent. After its removal from the system, the particles are stabilized by dodecanethiol molecules, which enable their very good dispersion in toluene solution. A digestive ripening procedure is carried out with the gold−toluene colloid, and for this purpose pure toluene as solvent is necessary. This has a dramatic effect on the n...

Solvation and hydration of proteins and nucleic acids: a theoretical view of simulation and experiment.

Abstract: Many theoretical, computational, and experimental techniques recently have been successfully used for description of the solvent distribution around macromolecules. In this Account, we consider recent developments in the areas of protein and nucleic acid solvation and hydration as seen by experiment, theory, and simulations. We find that in most cases not only the general phenomena of solvation but even local hydration patterns are more accurately discussed in the context of water distributions rather than individual molecules of water. While a few localized or highresidency waters are often associated with macromolecules in solution (or crystals from aqueous liquors), these are readily and accurately included in this more general description. The goal of this Account is to review the theoretical models used for the description of the interfacial solvent structure on the border near DNA and protein molecules. In particular, we hope to highlight the progress in this field over the past five years with a focus on comparison of simulation and experimental results.

Evaluation of a fast implicit solvent model for molecular dynamics simulations

Abstract: A solvation term based on the solvent accessible surface area (SASA) is combined with the CHARMM polar hydrogen force field for the efficient simulation of peptides and small proteins in aqueous solution. Only two atomic solvation parameters are used: one is negative for favoring the direct solvation of polar groups and the other positive for taking into account the hydrophobic effect on apolar groups. To approximate the water screening effects on the intrasolute electrostatic interactions, a distance-dependent dielectric function is used and ionic side chains are neutralized. The use of an analytical approximation of the SASA renders the model extremely efficient (i.e., only about 50% slower than in vacuo simulations). The limitations and range of applicability of the SASA model are assessed by simulations of proteins and structured peptides. For the latter, the present study and results reported elsewhere show that with the SASA model it is possible to sample a significant amount of folding/unfolding transitions, which permit the study of the thermodynamics and kinetics of folding at an atomic level of detail.

Detailed unfolding and folding of gaseous ubiquitin ions characterized by electron capture dissociation.

Abstract: The unfolding enthalpy of the native state of ubiquitin in solution is 5 to 8 times that of its gaseous ions, as determined by electron capture dissociation (ECD) mass spectrometry. Although two-state folding occurs in solution, the three-state gaseous process proposed for this by Clemmer and co-workers based on ion mobility data is supported in general by ECD mass spectra, including relative product yields, distinct Delta H(unfolding) values between states, site-specific melting temperatures, and folding kinetics indicating a cooperative process. ECD also confirms that the 13+ ions represent separate conformers, possibly with side-chain solvated alpha-helical structures. However, the ECD data on the noncovalent bonding in the 5+ to 13+ ions, determined overall in 69 of the 75 interresidue sites, shows that thermal unfolding proceeds via a diversity of intermediates whose conformational characteristics also depend on charge site locations. As occurs with increased acidity in solution, adding 6 protons to the 5+ ions completely destroys their tertiary noncovalent bonding. However, solvation of the newly protonated sites to the backbone instead increases the stability of the secondary structure (possibly an alpha-helix) of these gaseous ions, while in solution these new sites aid denaturation by solvation in the aqueous medium. Extensive ion equilibration can lead to even more compact and diverse conformers. The three-state unfolding of gaseous ubiquitin appears to involve ensembles of individual chain conformations in a "folding funnel" of parallel reaction paths. This also provides a further caution for characterizing solution conformers from their gas-phase behavior.

Computational alanine scanning of the 1:1 human growth hormone–receptor complex

Abstract: The MM-PBSA (Molecular Mechanics-Poisson-Boltzmann surface area) method was applied to the human Growth Hormone (hGH) complexed with its receptor to assess both the validity and the limitations of the computational alanine scanning approach. A 400-ps dynamical trajectory of the fully solvated complex was simulated at 300 K in a 101 A x 81 A x 107 A water box using periodic boundary conditions. Long-range electrostatic interactions were treated with the particle mesh Ewald (PME) summation method. Equally spaced snapshots along the trajectory were chosen to compute the binding free energy using a continuum solvation model to calculate the electrostatic desolvation free energy and a solvent-accessible surface area approach to treat the nonpolar solvation free energy. Computational alanine scanning was performed on the same set of snapshots by mutating the residues in the structural epitope of the hormone and the receptor to alanine and recomputing the deltaGbinding. To further investigate a particular structure, a 200-ps dynamical trajectory of an R43A hormone-receptor complex was simulated. By postprocessing a single trajectory of the wild-type complex, the average unsigned error of our calculated deltadeltaGbinding is approximately1 kcal/mol for the alanine mutations of hydrophobic residues and polar/charged residues without buried salt bridges. When residues involved in buried salt bridges are mutated to alanine, it is demonstrated that a separate trajectory of the alanine mutant complex can lead to reasonable agreement with experimental results. Our approach can be extended to rapid screening of a variety of possible modifications to binding sites.

Theoretical Calculation of pKa Using the Cluster−Continuum Model

Abstract: The pKa's of 17 species from −10 to 50 were calculated using the ab initio MP2/6-311+G(2df,2p) level of theory and inclusion of solvent effects by the cluster−continuum model, a hybrid approach that combines gas-phase clustering by explicit solvent molecules and solvation of the cluster by the dielectric continuum. In addition, the pure continuum methods SM5.42R and PCM were also used for comparison purposes. Species such as alcohols, carboxylic acids, phenol, acetaldehyde and its hydrate, thiols, hydrochloric acid, amines, and ethane were included. Our results show that the cluster−continuum model yields much better agreement with experiment than do the above-mentioned pure continuum methods, with a rms error of 2.2 pKa units as opposed to 7 pKa units for the SM5.42R and PCM methods. The good performance of the cluster−continuum model can be attributed to the introduction of strong and specific solute−solvent interactions with the molecules in the first solvation shell of ions. This feature decreases the...

Cooperative C−H···O Hydrogen Bonding in CO2−Lewis Base Complexes: Implications for Solvation in Supercritical CO2

Abstract: Understanding the fundamental principles for the design of CO2-philic materials is of growing importance due to the potential for enabling “green” chemistry and technologies in liquid and supercritical CO2 as alternative solvent systems. Recently, there have been numerous efforts to develop hydrocarbon-based CO2-philes containing carbonyl groups, which are known to interact through a Lewis acid−Lewis base (LA−LB) interaction with CO2 molecules, thereby providing the necessary solvation energy for dissolution. In this work, we investigate the role of a weaker, but cooperative, C−H···O hydrogen bond as an additional stabilizing interaction in the solvation of polycarbonyl moieties with hydrogen atoms attached directly to the carbonyl carbon or to the α-carbon atom. Ab initio calculations are performed on simple intermolecular complexes of CO2 with compounds capable of acting as Lewis bases. Systems studied in different interaction configurations include formaldehyde, acetaldehyde, acetic acid, and methyl ac...

Mechanism for Damage to DNA by Low-Energy Electrons †

Abstract: We have carried out ab initio electronic structure calculations on a portion of DNA, the results of which provide support for a mechanism that produces single-strand breaks (SSBs) with low-energy electrons. This mechanism involves attaching a low-energy electron (ca. 1 eV) to a π* orbital of a DNA base to form a shape-resonance state. This π* anion then undergoes a sugar−phosphate C−O bond rupture over a small barrier to produce SSBs. In addition to supporting the efficacy of such a mechanism, our results suggest that solvation plays a crucial role in the rate of SSB formation when such very short-lived shape resonances are involved. In particular, they suggest that either the π* anion must be rendered electronically stable by solvation or its detachment lifetime must be several orders of magnitude longer in the solvated species than in the nonsolvated species.

Solvation Dynamics of Coumarin-153 in a Room-Temperature Ionic Liquid

Abstract: Room-temperature ionic liquids are rapidly emerging as a new class of medium that is ideally suited for carrying out chemical reactions and various other applications. In this paper, steady-state and time-resolved fluorescence behavior of coumarin-153 (C153) have been reported in a room-temperature ionic liquid, 1-butyl-3-methylimidazolium tetrafluoroborate or [BMIM][BF4]. The polarity of the solvent, as estimated from the fluorescence maximum of C153, is found to be 48.9 on the ET(30) polarity scale. The fluorescence decay behavior of C153 in [BMIM][BF4] is found to be dependent on the monitoring wavelength. Although the time dependence of fluorescence in the blue region of the spectrum is represented by a multicomponent decay, that in the red region of the spectrum consists of clear growth followed by decay. The time-dependent evolution of the fluorescence spectrum of C153, constructed from the decay profiles at several wavelengths, indicates biphasic solvation dynamics similar to that observed in the c...

The SGB/NP hydration free energy model based on the surface generalized born solvent reaction field and novel nonpolar hydration free energy estimators

Abstract: The development and parameterization of a solvent potential of mean force designed to reproduce the hydration thermodynamics of small molecules and macromolecules aimed toward applications in conformation prediction and ligand binding free energy prediction is presented. The model, named SGB/NP, is based on a parameterization of the Surface Generalized Born continuum dielectric electrostatic model using explicit solvent free energy perturbation calculations and a newly developed nonpolar hydration free energy estimator motivated by the results of explicit solvent simulations of the thermodynamics of hydration of hydrocarbons. The nonpolar model contains, in addition to the more commonly used solvent accessible surface area term, a component corresponding to the attractive solute-solvent interactions. This term is found to be important to improve the accuracy of the model, particularly for cyclic and hydrogen bonding compounds. The model is parameterized against the experimental hydration free energies of a set of small organic molecules. The model reproduces the experimental hydration free energies of small organic molecules with an accuracy comparable or superior to similar models employing more computationally demanding estimators and/or a more extensive set of parameters.

Accurate Prediction of Acidity Constants in Aqueous Solution via Density Functional Theory and Self-Consistent Reaction Field Methods

Abstract: We have developed a protocol for computing the acidity constant (pKa) of organic compounds via ab initio quantum chemistry and continuum solvation methods. Density functional (DFT) calculations employing large basis sets are used to determine the gas-phase deprotonation energies. Solvation effects are treated via a self-consistent reaction field (SCRF) formalism involving accurate numerical solution of the Poisson−Boltzmann equation. Dielectric radii are parametrized for each functional group of interest to optimize solvation free energy calculations for neutral and charged species. While the intrinsic accuracy of these approaches is quite impressive (errors on the order of a few kcal/mol), it is not quite good enough to achieve the target accuracy that we have set for pKa prediction of 0.5 pKa units. Consequently, two further empirical parameters, scaling and additive factors, are determined for every functional group of interest by linear fitting directly to pKa data for a training set. With this additi...

Secondary and tertiary structures of gaseous protein ions characterized by electron capture dissociation mass spectrometry and photofragment spectroscopy.

Abstract: Over the last decade a variety of MS measurements, such as H/D exchange, collision cross sections, and electron capture dissociation (ECD), have been used to characterize protein folding in the gas phase, in the absence of solvent. To the extensive data already available on ubiquitin, here photofragmentation of its ECD-reduced (M + nH)(n−1)+• ions shows that only the 6+ to 9+, not the 10+ to 13+ ions, have tertiary noncovalent bonding; this is indicated as hydrogen bonding by the 3,050–3,775 cm−1 photofragment spectrum. ECD spectra and H/D exchange of the 13+ ions are consistent with an all α-helical secondary structure, with the 11+ and 10+ ions sufficiently destabilized to denature small bend regions near the helix termini. In the 8+ and 9+ ions these terminal helical regions are folded over to be antiparallel and noncovalently bonded to part of the central helix, whereas this overlap is extended in the 7+, 6+, and, presumably, 5+ ions to form a highly stable three-helix bundle. Thermal denaturing of the 7+ to 9+ conformers both peels and slides back the outer helices from the central one, but for the 6+ conformer, this instead extends the protein ends away to shrink the three-helix bundle. Thus removal of H2O from a native protein negates hydrophobic interactions, preferentially stabilizes the α-helical secondary structure with direct solvation of additional protons, and increases tertiary interhelix dipole-dipole and hydrogen bonding.

Computation of pKa from Dielectric Continuum Theory

Abstract: This work considers calculation of pKa for a series of related alcohols, carboxylic acids, and ammonium ions spanning a wide range of acidities, using quantum mechanical treatment of solute electronic structure in conjunction with a dielectric continuum model for solvation of each bare solute. The electronic structure methods used are of sufficiently high quality to give very good agreement with experimental gas phase acidities. Dielectric continuum theory of solvation is used in a recently developed form that accurately takes account of solute charge density penetrating outside the solvent cavity that nominally encloses it. The cavity surface is defined by a single parameter characterizing an electronic isodensity contour, and contours are examined at and near the value 0.001 e/ that has previously led to a good account of solvation effects on properties of neutral solutes in various solvents. In water, the pKa values calculated for alcohols and carboxylic acids are generally much higher than experiment,...