Showing papers on "Implicit solvation published in 2005"

COSMO-RS: From Quantum Chemistry to Fluid Phase Thermodynamics and Drug Design

Abstract: 1. Introduction 2. Dielectric Continuum Solvation Models and COSMO 3. Fundamental Criticism of the Dielectric Continuum Approach 4. Molecular Interactions at the North Pole: A Virtual Experiment 5. Statistical Thermodynamics of Interacting Surfaces 6. The Basic COSMO-RS 7. Refinements, Parameterization, and the Complete COSMO-RS 8. COSMO-RS for Chemical Engineering Thermodynamics 9. The -moment approach 10. The wider range of COSMO-RS applicability 11. Life-Science Applications of COSMO-RS 12. Summary, Limitations, and Perspectives

SM6: A Density Functional Theory Continuum Solvation Model for Calculating Aqueous Solvation Free Energies of Neutrals, Ions, and Solute-Water Clusters.

Abstract: A new charge model, called Charge Model 4 (CM4), and a new continuum solvent model, called Solvation Model 6 (SM6), are presented Using a database of aqueous solvation free energies for 273 neutrals, 112 ions, and 31 ion−water clusters, parameter sets for the mPW0 hybrid density functional of Adamo and Barone (Adamo, C; Barone, V J Chem Phys 1998, 108, 664−675) were optimized for use with the following four basis sets: MIDI!6D, 6-31G(d), 6-31+G(d), and 6-31+G(d,p) SM6 separates the observable aqueous solvation free energy into two different components: one arising from long-range bulk electrostatic effects and a second from short-range interactions between the solute and solvent molecules in the first solvation shell This partition of the observable solvation free energy allows SM6 to effectively model a wide range of solutes For the 273 neutral solutes in the test set, SM6 achieves an average error of ∼050 kcal/mol in the aqueous solvation free energies For solutes, especially ions, that hav

Quantum-Chemical Predictions of Absolute Standard Redox Potentials of Diverse Organic Molecules and Free Radicals in Acetonitrile

Abstract: A calibrated B3LYP/6-311++G(2df,2p)//B3LYP/6-31+G(d) method was found to be able to predict the gas-phase adiabatic ionization potentials of 160 structurally unrelated organic molecules with a precision of 0.14 eV. A PCM solvation model was benchmarked that could predict the pK(a)'s of 15 organic acids in acetonitrile with a precision of 1.0 pK(a) unit. Combining the above two methods, we developed a generally applicable protocol that could successfully predict the standard redox potentials of 270 structurally unrelated organic molecules in acetonitrile. The standard deviation of the predictions was 0.17 V. The study demonstrated that computational electrochemistry could become a powerful tool for the organic chemical community. It also confirmed that the continuum solvation theory could correctly predict the solvation energies of organic radicals. Finally, with the help of the newly developed protocol we were able to establish a scale of standard redox potentials for diverse types of organic free radicals for the first time. Knowledge about these redox potentials should be of great value for understanding the numerous electron-transfer reactions in organic and bioorganic chemistry.

Electronic excitation energies of molecules in solution: state specific and linear response methods for nonequilibrium continuum solvation models.

Abstract: We present a formal comparison between the two different approaches to the calculation of electronic excitation energies of molecules in solution within the continuum solvation model framework, taking also into account nonequilibrium effects. These two approaches, one based on the explicit evaluation of the excited state wave function of the solute and the other based on the linear response theory, are here proven to give formally different expressions for the excitation energies even when exact eigenstates are considered. Calculations performed for some illustrative examples show that this formal difference has sensible effects on absolute solvatochromic shifts (i.e., with respect to gas phase) while it has small effects on relative (i.e., nonpolar to polar solvent) solvatochromic shifts.

Density functional studies of actinyl aquo complexes studied using small-core effective core potentials and a scalar four-component relativistic method.

Abstract: The title compounds, [AnO(2)(H(2)O)(5)](n)(+), n = 1 or 2 and An = U, Np, and Pu, are studied using relativistic density functional theory (DFT). Three rather different relativistic methods are used, small-core effective core potentials (SC-ECP), a scalar four-component all-electron relativistic method, and the zeroeth-order regular approximation. The methods provide similar results for a variety of properties, giving confidence in their accuracy. Spin-orbit and multiplet corrections to the An(VI)/An(V) reduction potential are added in an approximate fashion but are found to be essential. Bulk solvation effects are modeled with continuum solvation models (CPCM, COSMO). These models are tested by comparing explicit (cluster), continuum, and mixed cluster/continuum solvation models as applied to various properties. The continuum solvation models are shown to accurately account for the effects of the solvent, provided that at least the first coordination sphere is included. Reoptimizing the structures in the presence of the bulk solvent is seen to be important for the equatorial bond lengths but less relevant for energetics. Explicit inclusion of waters in the second coordination sphere has a modest influence on the energetics. For the first time, free energies of solvation are calculated for all six [AnO(2)(H(2)O)(5)](n)(+) species. The calculated numbers are within the experimental error margins, and the experimental trend is reproduced correctly. By comparison of different relativistic methods, it is shown that an accurate relativistic description leads to marked improvements over the older large-core ECP (LC-ECP) method for bond lengths, vibrational frequencies, and, in particular, the An(VI)/An(V) reduction potential. Two approximate DFT methods are compared, B3LYP, a hybrid DFT method, and PBE, a generalized gradient approximation. Either method yields An(VI)/An(V) reduction potentials of comparable quality. Overall, the experimental reduction potentials are accurately reproduced by the calculations.

Electronic excitation energies of molecules in solution within continuum solvation models: investigating the discrepancy between state-specific and linear-response methods.

Abstract: In a recent article [R. Cammi, S. Corni, B. Mennucci, and J. Tomasi, J. Chem. Phys. 122, 104513 (2005)], we demonstrated that the state-specific (SS) and the linear-response (LR) approaches, two different ways to calculate solute excitation energies in the framework of quantum-mechanical continuum models of solvation, give different excitation energy expressions. In particular, they differ in the terms related to the electronic response of the solvent. In the present work, we further investigate this difference by comparing the excitation energy expressions of SS and LR with those obtained through a simple model for solute-solvent systems that bypasses one of the basic assumptions of continuum solvation models, i.e., the use of a single Hartree product of a solute and a solvent wave function to describe the total solute-solvent wave function. In particular, we consider the total solute-solvent wave function as a linear combination of the four products of two solute states and two solvent electronic states. To maximize the comparability with quantum-mechanical continuum model the resulting excitation energy expression is recast in terms of response functions of the solvent and quantities proper for the solvated molecule. The comparison of the presented expressions with the LR and SS ones enlightens the physical meaning of the terms included or neglected by these approaches and shows that SS agrees with the results of the four-level model, while LR includes a term classified as dispersion in previous treatments and neglects another related to electrostatic. A discussion on the possible origin of the LR flaw is finally given.

A generalized Born formalism for heterogeneous dielectric environments: application to the implicit modeling of biological membranes.

Abstract: Reliable computer simulations of complex biological environments such as integral membrane proteins with explicit water and lipid molecules remain a challenging task. We propose a modification of the standard generalized Born theory of homogeneous solvent for modeling the heterogeneous dielectric environments such as lipid/water interfaces. Our model allows the representation of biological membranes in the form of multiple layered dielectric regions with dielectric constants that are different from the solute cavity. The proposed new formalism is shown to predict the electrostatic component of solvation free energy with a relative error of 0.17% compared to exact finite-difference solutions of the Poisson equation for a transmembrane helix test system. Molecular dynamics simulations of melittin and bacteriorhodopsin are carried out and performed over 10 ns and 7 ns of simulation time, respectively. The center of melittin along the membrane normal in these stable simulations is in excellent agreement with the relevant experimental data. Simulations of bacteriorhodopsin started from the experimental structure remained stable and in close agreement with experiment. We also examined the free energy profiles of water and amino acid side chain analogs upon membrane insertion. The results with our implicit membrane model agree well with the experimental transfer free energy data from cyclohexane to water as well as explicit solvent simulations of water and selected side chain analogs.

Solvation dynamics in reverse micelles: the role of headgroup-solute interactions.

Abstract: We present molecular dynamics simulation results for solvation dynamics in the water pool of anionicsurfactant reverse micelles (RMs) of varying water content, w0. The model RMs are designed to represent water/aerosol-OT/oil systems, where aerosol-OT is the common name for sodium bis(2-ethylhexyl)sulfosuccinate. To determine the effects of chromophore-headgroup interactions on solvation dynamics, we compare the results for charge localization in model ionic diatomic chromophores that differ only in charge sign. Electronic excitation in both cases is modeled as charge localization on one of the solute sites. We find dramatic differences in the solvation responses for anionic and cationic chromophores. Solvation dynamics for the cationic chromophore are considerably slower and more strongly w0-dependent than those for the anionic chromophore. Further analysis indicates that the difference in the responses can be ascribed in part to the different initial locations of the two chromophores relative to the surfactant interface. In addition, slow motion of the cationic chromophore relative to the interface is the main contributor to the longer-time decay of the solvation response to charge localization in this case.

Dependence of ion hydration on the sign of the ion's charge.

Abstract: The solvation of simple ions in water is studied using molecular dynamics simulations with a polarizable force field. Previous simulations using this potential demonstrated that anions are more favorably solvated in water than cations. The present work is an attempt to explain this result by examining the effects of ions on the surrounding water structure, with particular focus on the first solvation shell and its interactions with the surrounding water. We conclude that while the first solvation shell surrounding cations is frustrated by competition between ion-water and water-water interactions, solvation of anions is compatible with good water-water interactions.

Protein/ligand binding free energies calculated with quantum mechanics/molecular mechanics

Abstract: The calculation of binding affinities for flexible ligands has hitherto required the availability of reliable molecular mechanics parameters for the ligands, a restriction that can in principle be lifted by using a mixed quantum mechanics/molecular mechanics (QM/MM) representation in which the ligand is treated quantum mechanically. The feasibility of this approach is evaluated here, combining QM/MM with the Poisson-Boltzmann/surface area model of continuum solvation and testing the method on a set of 47 benzamidine derivatives binding to trypsin. The experimental range of the absolute binding energy (DeltaG = -3.9 to -7.6 kcal/mol) is reproduced well, with a root-mean-square (RMS) error of 1.2 kcal/mol. When QM/MM is applied without reoptimization to the very different ligands of FK506 binding protein the RMS error is only 0.7 kcal/mol. The results show that QM/MM is a promising new avenue for automated docking and scoring of flexible ligands. Suggestions are made for further improvements in accuracy.

A molecular dynamics computer simulation study of room-temperature ionic liquids. II. Equilibrium and nonequilibrium solvation dynamics.

Abstract: The molecular dynamics (MD) simulation study of solvation structure and free energetics in 1-ethyl-3-methylimidazolium chloride and 1-ethyl-3-methylimidazolium hexafluorophosphate using a probe solute in the preceding article [Y. Shim, M. Y. Choi and H. J. Kim, J. Chem. Phys. 122, 044510 (2005)] is extended to investigate dynamic properties of these liquids. Solvent fluctuation dynamics near equilibrium are studied via MD and associated time-dependent friction is analyzed via the generalized Langevin equation. Nonequilibrium solvent relaxation following an instantaneous change in the solute charge distribution and accompanying solvent structure reorganization are also investigated. Both equilibrium and nonequilibrium solvation dynamics are characterized by at least two vastly different time scales--a subpicosecond inertial regime followed by a slow diffusive regime. Solvent regions contributing to the subpicosecond nonequilibrium relaxation are found to vary significantly with initial solvation configurations, especially near the solute. If the solvent density near the solute is sufficiently high at the outset of the relaxation, subpicosecond dynamics are mainly governed by the motions of a few ions close to the solute. By contrast, in the case of a low local density, solvent ions located not only close to but also relatively far from the solute participate in the subpicosecond relaxation. Despite this difference, linear response holds reasonably well in both ionic liquids.

A Polarizable Force Field and Continuum Solvation Methodology for Modeling of Protein-Ligand Interactions.

Abstract: A polarizable force field, and associated continuum solvation model, have been developed for the explicit purpose of computing and studying the energetics and structural features of protein binding to the wide range of ligands with potential for medicinal applications. Parameters for the polarizable force field (PFF) are derived from gas-phase ab initio calculations and then utilized for applications in which the protein binding to ligands occurs in aqueous solvents, wherein the charge distributions of proteins and ligands can be dramatically altered. The continuum solvation model is based on a self-consistent reaction field description of solvation, incorporating an analytical gradient, that allows energy minimizations (and, potentially, molecular dynamics simulations) of protein/ligand systems in continuum solvent. This technology includes a nonpolar model describing the cost of cavity formation, and van der Waals interactions, between the continuum solvent and protein/ligand solutes. Tests of the structural accuracy and computational stability of the methodology, and timings for energy minimizations of proteins and protein/ligand systems in the condensed phase, are reported. In addition, the derivation of polarizability, electrostatic, exchange repulsion, and torsion parameters from ab initio data is described, along with the use of experimental solvation energies for determining parameters for the solvation model.

Sensitivity of polar solvation dynamics to the secondary structures of aqueous proteins and the role of surface exposure of the probe.

Abstract: The structure and dynamics of water around a protein is expected to be sensitive to the details of the adjacent secondary structure of the protein. In this article, we explore this sensitivity by calculating both the orientational dynamics of the surface water molecules and the equilibrium solvation time correlation function of the polar amino acid residues in each of the three helical segments of the protein HP-36, using atomistic molecular dynamics simulations. The solvation dynamics of polar amino acid residues in helix-2 is found to be faster than that of the other two helices (the average time constant is smaller by a factor of 2), although the interfacial water molecules around helix-2 exhibit much slower orientational dynamics than that around the other two helices. A careful analysis shows that the origin of such a counterintuitive behavior lies in the dependence of the solvation time correlation function on the surface exposure of the probe-the more exposed is the probe, the faster the solvation dynamics. We discuss that these results are useful in explaining recent solvation dynamics experiments.

Density Functional Theory of Solvation and Its Relation to Implicit Solvent Models

Abstract: We describe a density functional theory approach to solvation in molecular solvents. The solvation free energy of a complex solute can be obtained by direct minimization of a density functional, instead of the thermodynamic integration scheme necessary when using atomistic simulations. In the homogeneous reference fluid approximation, the expression of the free-energy functional relies on the knowledge of the direct correlation function of the pure solvent. After discussing general molecular solvents, we present a generic density functional describing a dipolar solvent and we show how it can be reduced to the conventional implicit solvent models when the solvent microscopic structure is neglected. With respect to those models, the functional includes additional effects such as the microscopic structure of the solvent, the dipolar saturation effect, and the nonlocal character of the dielectric constant. We also show how this functional can be minimized numerically on a three-dimensional grid around a solute of complex shape to provide, in a single shot, both the average solvent structure and the absolute solvation free energy.

A molecular dynamics computer simulation study of room-temperature ionic liquids. I. Equilibrium solvation structure and free energetics.

Abstract: Solvation in 1-ethyl-3-methylmidazolium chloride and in 1-ethyl-3-methylimidazolium hexafluorophosphate near equilibrium is investigated via molecular dynamics computer simulations with diatomic and benzenelike molecules employed as probe solutes. It is found that electrostriction plays an important role in both solvation structure and free energetics. The angular and radial distributions of cations and anions become more structured and their densities near the solute become enhanced as the solute charge separation grows. Due to the enhancement in structural rigidity induced by electrostriction, the force constant associated with solvent configuration fluctuations relevant to charge shift and transfer processes is also found to increase. The effective polarity and reorganization free energies of these ionic liquids are analyzed and compared with those of highly polar acetonitrile. Their screening behavior of electric charges is also investigated.

Surface solvation for an ion in a water cluster

Abstract: We have used molecular dynamics simulations to study the structural, dynamical, and thermodynamical properties of ions in water clusters. Careful evaluations of the free energy, internal energy, and entropy are used to address controversial or unresolved issues, related to the underlying physical cause of surface solvation, and the basic assumptions that go with it. Our main conclusions are the following. (i) The main cause of surface solvation of a single ion in a water cluster is both water and ion polarization, coupled to the charge and size of the ion. Interestingly, the total energy of the ion increases near the cluster surface, while the total energy of water decreases. Also, our analysis clearly shows that the cause of surface solvation is not the size of the total water dipole (unless this is too small). (ii) The entropic contribution is the same order of magnitude as the energetic contribution, and therefore cannot be neglected for quantitative results. (iii) A pure energetic analysis can give a qualitative description of the ion position at room temperature. (iv) We have observed surface solvation of a large positive iodinelike ion in a polarizable water cluster, but not in a nonpolarizable water cluster.

Theoretical study of the effects of solvent environment on photophysical properties and electronic structure of paracyclophane chromophores

Abstract: We use first-principles quantum-chemical approaches to study absorption and emission properties of recently synthesized distyrylbenzene (DSB) derivative chromophores and their dimers (two DSB molecules linked through a [2.2]paracyclophane moiety). Several solvent models are applied to model experimentally observed shifts and radiative lifetimes in Stokes nonpolar organic solvents (toluene) and water. The molecular environment is simulated using the implicit solvation models, as well as explicit water molecules and counterions. Calculations show that neither implicit nor explicit solvent models are sufficient to reproduce experimental observations. The contact pair between the chromophore and counterion, on the other hand, is able to reproduce the experimental data when a partial screening effect of the solvent is taken into account. Based on our simulations we suggest two mechanisms for the excited-state lifetime increase in aqueous solutions. These findings may have a number of implications for organic light-emitting devices, electronic functionalities of soluble polymers and molecular fluorescent labels, and their possible applications as biosensors and charge/energy conduits in nanoassemblies.

Pseudorotation barriers of biological oxyphosphoranes: a challenge for simulations of ribozyme catalysis.

Abstract: Pseudorotation reactions of biologically relevant oxyphosphoranes were studied by using density functional and continuum solvation methods. A series of 16 pseudorotation reactions involving acyclic and cyclic oxyphosphoranes in neutral and monoanionic (singly deprotonated) forms were studied, in addition to pseudorotation of PF5. The effect of solvent was treated by using three different solvation models for comparison. The barriers to pseudorotation ranged from 1.5 to 8.1 kcal mol(-1) and were influenced systematically by charge state, apicophilicity of ligands, intramolecular hydrogen bonding, cyclic structure and solvation. Barriers to pseudorotation for monoanionic phosphoranes occur with the anionic oxo ligand as the pivotal atom, and are generally lower than for neutral phosphoranes. The OCH3 groups were observed to be more apicophilic than OH groups, and hence pseudorotations that involve axial OCH3/equatorial OH exchange had higher reaction and activation free energy values. Solvent generally lowered barriers relative to the gas-phase reactions. These results, together with isotope 18O exchange experiments, support the assertion that dianionic phosphoranes are not sufficiently long-lived to undergo pseudorotation. Comparison of the density functional results with those from several semiempirical quantum models highlight a challenge for new-generation hybrid quantum mechanical/molecular mechanical potentials for non-enzymatic and enzymatic phosphoryl transfer reactions: the reliable modeling of pseudorotation processes.

Direct correlation functions and the density functional theory of polar solvents

Abstract: To describe the solvation properties of polar or charged species, and the reaction free-energy of charge transfers, we propose a generalization of the Marcus electrostatic polarization free-energy functional which accounts for the molecular nature of the solvent. The proposed generic free energy functional relies crucially on the knowledge of the direct correlation function of the homogeneous solvent. For the case of a dipolar solvent, we show how this fundamental quantity can be extracted directly from molecular dynamics simulations of the pure solvent instead of the traditional route of integral equation theories. The direct correlation function computed from simulation is compared to approximate ones obtained from linearized and quadratic HNC integral closures. The performance of the corresponding density functionals is assessed, in comparison to “exact” molecular dynamics results, for the solvation free-energies and the solvent density profiles around simple molecular solutes.

Biomolecular Applications of Poisson–Boltzmann Methods

Abstract: Throughout the 1990s, biomolecular simulation has become increasingly commonplace in biology and has gained acceptance as an important biophysical method for understanding molecular structure, dynamics, and function. The energetic properties of a biomolecule are determined by a combination of both shortand long-range forces. Short-range forces include several components, such as van der Waals, bonding forces, angular forces, and torsional interactions. Long-range forces, on the other hand, are typically dominated by electrostatic interactions. Because of their slow decay over distance, electrostatics cannot be neglected or truncated in biomolecular modeling; these forces contribute significantly to molecular interactions at all length scales. As such, methods that enable the accurate and efficient modeling of these interactions are of central importance in molecular simulation. The exact behavior of electrostatic interactions in a simulation is generally determined by four factors: molecular charge distributions, solute atomic radii, mobile ionic species, and solvent. Molecular charge distributions are

Prediction of the orientations of adsorbed protein using an empirical energy function with implicit solvation.

Abstract: When simulating protein adsorption behavior, decisions must first be made regarding how the protein should be oriented on the surface. To address this problem, we have developed a molecular simulation program that combines an empirical adsorption free energy function with an efficient configurational search method to calculate orientation-dependent adsorption free energies between proteins and functionalized surfaces. The configuration space is searched systematically using a quaternion rotation technique, and the adsorption free energy is evaluated using an empirical energy function with an efficient grid-based calculational method. In this paper, the developed method is applied to analyze the preferred orientations of a model protein, lysozyme, on various functionalized alkanethiol self-assembled monolayer (SAM) surfaces by the generation of contour graphs that relate adsorption free energy to adsorbed orientation, and the results are compared with experimental observations. As anticipated, the adsorbed orientation of lysozyme is predicted to be dependent on the discrete organization of the functional groups presented by the surface. Lysozyme, which is a positively charged protein, is predicted to adsorb on its 'side' on both hydrophobic and negatively charged surfaces. On surfaces with discrete positively charged sites, attractive interaction energies can also be obtained due to the presence of discrete local negative charges present on the lysozyme surface. In this case, 'end-on' orientations are preferred. Additionally, SAM surface models with mixed functionality suggest that the interactions between lysozyme and surfaces could be greatly enhanced if individual surface functional groups are able to access the catalytic cleft region of lysozyme, similar to ligand-receptor interactions. The contour graphs generated by this method can be used to identify low-energy orientations that can then be used as starting points for further simulations to investigate conformational changes induced in protein structure following initial adsorption.

On the coupling between molecular diffusion and solvation shell exchange.

Abstract: The connection between diffusion and solvent exchanges between first and second solvation shells is studied by means of molecular dynamics simulations and analytic calculations, with detailed illustrations for water exchange for the Li+ and Na+ ions, and for liquid argon. First, two methods are proposed which allow, by means of simulation, to extract the quantitative speed-up in diffusion induced by the exchange events. Second, it is shown by simple kinematic considerations that the instantaneous velocity of the solute conditions to a considerable extent the character of the exchanges. Analytic formulas are derived which quantitatively estimate this effect, and which are of general applicability to molecular diffusion in any thermal fluid. Despite the simplicity of the kinematic considerations, they are shown to well describe many aspects of solvent exchange/diffusion coupling features for nontrivial systems.

Absolute Calculations of Acidity of C-Substituted Tetrazoles in Solution

Abstract: The CBS-QB3 method was used to calculate the gas-phase free energy difference between nine tetrazole derivatives and their anions, and the DPCM and CPCM continuum solvation methods were applied to calculate the free energy differences of solvation. The calculations were performed on both gas-phase and solvent-phase optimized structures. Absolute pKa calculations using the CPCM method and the gas-phase optimized structures yielded mean unsigned error of 0.4 pKa unit. The calculations were made with the routine settings implemented in Gaussian 98. The study is as accurate as the best reported so far for six carboxylic acids and phenols and, to our knowledge, the best reported for the acidities of heterocyclic compounds in solution.

Local density profiles are coupled to solute size and attractive potential for nanoscopic hydrophobic solutes

Abstract: We employ constant pressure molecular dynamics simulations to investigate the effects of solute size and solute–water dispersion interactions on the solvation behavior of nanoscopic hydrophobic model solutes in water at normal temperature and pressure. The hydration behavior around a single planar atomic model solute as well as a pair of such solutes have been considered. The hydration water structure of a model nanoscopic solute with standard Lennard-Jones interaction is shown to be significantly different from that of their purely repulsive analogues. The density of water in the first solvation shell of a Lennard-Jones solute is much higher than that of bulk water and it remains almost unchanged with the increase of the solute dimensions from one to a few nanometers. On the other hand, for a purely repulsive analogue of the above model, solute hydration behavior shows a marked solute size dependence. The contact density of water in this case decreases with the increasing dimension of the solute. We also...

A novel quantum mechanical/molecular mechanical approach to the free energy calculation for isomerization of glycine in aqueous solution

Abstract: The free energy change associated with the isomerization reaction of glycine in water solution has been studied by a hybrid quantum mechanical/molecular mechanical (QM/MM) approach combined with the theory of energy representation (QM/MM-ER) recently developed. The solvation free energies for both neutral and zwitterionic form of glycine have been determined by means of the QM/MM-ER simulation. The contributions of the electronic polarization and the fluctuation of the QM solute to the solvation free energy have been investigated. It has been found that the contribution of the density fluctuation of the zwitterionic solute is estimated as −4.2kcal∕mol in the total solvation free energy of −46.1kcal∕mol, while that of the neutral form is computed as −3.0kcal∕mol in the solvation free energy of −15.6kcal∕mol. The resultant free energy change associated with the isomerization of glycine in water has been obtained as −7.8kcal∕mol, in excellent agreement with the experimental data of −7.3 or −7.7kcal∕mol, implying the accuracy of the QM/MM-ER approach. The results have also been compared with those computed by other methodologies such as the polarizable continuum model and the classical molecular simulation. The efficiency and advantage of the QM/MM-ER method has been discussed.

Density-functional theory and hybrid density-functional theory continuum solvation models for aqueous and organic solvents: universal SM5.43 and SM5.43R solvation models for any fraction of Hartree-Fock exchange

Abstract: Hybrid density functional theory, which is a combined Hartree–Fock and density functional method, provides a simple but effective way to incorporate nonlocal exchange effects and static and dynamical correlation energy into an orbital-based theory with affordable computational cost for many important problems of gas-phase chemistry. The inclusion of a reaction field representing an implicit solvent in a self-consistent hybrid density functional calculation provides an effective and efficient way to extend this approach to problems of liquid-phase chemistry. In previous work, we have parameterized several models based on this approach, and in the present article, we present several new parameterizations based on implicit solvation models SM5.43 and SM5.43R. In particular, we extend the applicability of these solvation models to several combinations of the MPWX hybrid-density functional with various one-electron basis sets, where MPWX denotes a combination of Barone and Adamo’s modified version of Perdew and Wang’s exchange functional, Perdew and Wang’s correlation functional, and a percentage X of exact Hartree–Fock exchange. SM5.43R parameter optimizations are presented for the MPWX/MIDI!, MPWX/MIDI!6D, and MPWX/6-31+G(d,p) combinations with X=0 (i.e., pure density functional theory), 25, 42.8, and 60.6, and for MPWX/6-31G(d) and MPWX/6-31+G(d), with X=0, 42.8, and 60.6; this constitutes a total of 18 new parameter sets. [Note that parameter optimizations using MPW25/6-31G(d) and MPW25/6-31+G(d) were carried out in a previous SM5.43R parameterization.] For each of the five basis sets, we found no significant loss in the accuracy of the model when parameters averaged over the four values of X are used instead of the parameters optimized for a specific value of X. Therefore for each of the five basis sets used here, the SM5.43R and SM5.43 models are defined to have a single parameter set that can be used for any value of X between 0 and 60.6. The new models yield accurate free energies of solvation for a broad range of solutes in both water and organic solvents. On the average, the mean-unsigned errors, as compared with those from experiment, of the free energies of solvation of neutral solutes range from 0.50 to 0.55 kcal/mol and those for ions range from 4.5 to 4.9 kcal/mol. Since the SM5.43R model computes the free energy of solvation as a sum of bulk-electrostatic and non-bulk-electrostatic contributions, it may be used for detailed analysis of the physical effects underlying a calculation of the free energy of solvation. Several calculations illustrating the partitioning of these contributions for a variety of solutes in n-hexadecane, 1-octanol, and water are presented.

Free energy surfaces of miniproteins with a ββα motif: Replica exchange molecular dynamics simulation with an implicit solvation model

Abstract: Designed miniproteins with a betabetaalpha motif, such as BBA5, 1FSD, and 1PSV can serve as a benchmark set to test the validity of all-atom force fields with computer simulation, because they contain all the basic structural elements in protein folding. Unfortunately, it was found that the standard all-atom force fields with the generalized Born (GB) implicit solvation model tend to produce distorted free energy surfaces for the betabetaalpha proteins, not only because energetically those proteins need to be described by more balanced weights of the alpha- and beta-strands, but also because the GB implicit solvation model suffers from overestimated salt bridge effects. In an attempt to resolve these problems, we have modified one of the standard all-atom force fields in conjunction with the GB model, such that each native state of the betabetaalpha proteins is in its free energy minimum state with reasonable energy barriers separating local minima. With this modified energy model, the free energy contour map in each protein was constructed from the replica exchange molecular dynamics REMD simulation. The resulting free energy surfaces are significantly improved in comparison with previous simulation results and consistent with general views on small protein folding behaviors with realistic topology and energetics of all three proteins.

Design of an organocatalyst for ion–molecule SN2 reactions: A new solvent effect on the reaction rate predicted by ab initio calculations

Abstract: Using ab initio calculations coupled with a continuum solvation model (PCM), it was shown that an organic molecule, 1,4-benzenedimethanol, is able to make two hydrogen bonds with anion–molecule S N 2 transition states. We have investigated the catalytic properties of this species for the S N 2 reaction between acetate ion and ethyl chloride in DMSO solution. Our calculations predicts an activation free energy barrier of 26.1 kcal mol −1 for the uncatalyzed mechanism and 20.2 kcal mol −1 for the catalyzed mechanism, a drop in the activation barrier in relation to free reactants by 5.9 kcal mol −1 . This organocatalyst is also able to catalyze E2 reactions and for the present system, the free energy barrier for the E2 mechanism drops by 5.3 kcal mol −1 due the action of the catalyst. Based on our theoretical data and even considering the formation of a complex between the acetate ion and the catalyst, we have estimated that the 1,4-benzenedimethanol mixed with the DMSO solvent should result in a powerful new solvent system, able to accelerate S N 2 reactions by a factor as large as 10 3 in relation to pure DMSO.