Statistical-mechanical liquid theories reproduce anomalous thermodynamic properties of explicit two-dimensional water models.

We have developed an analytical theory for a simple model of liquid water. We apply Wertheim's thermodynamic perturbation theory (TPT) and integral equation theory (IET) for associative liquids to the rose model, which is among the simplest models of water. The particles interact through rose potentials for orientation dependent pairwise interactions. Modifying both the shape and range of a three-petal rose function, we construct an efficient and dynamical mimic of the two-dimensional (2D) Mercedes-Benz (MB) water model. The particles in 2D MB are 2D Lennard-Jones disks with three hydrogen bonding arms arranged symmetrically, resembling the Mercedes-Benz logo. Both models qualitatively predict both the anomalous properties of pure water and the anomalous solvation thermodynamics of nonpolar molecules. The IET is based on the orientationally averaged version of the Ornstein-Zernike equation. This is one of the main approximations in the present work. IET correctly predicts the pair correlation functions at high temperatures. Both TPT and IET are in semi-quantitative agreement with the Monte Carlo values of the molar volume, isothermal compressibility, thermal expansion coefficient, and heat capacity. A major advantage of these theories is that they require orders of magnitude less computer time than the Monte Carlo simulations.

Radical Perfluoroalkylation Enabled by a Catalytically Generated Halogen Bonding Complex and Visible Light Irradiation.

Exploiting charge-transfer complexes in visible light-promoted single-electron redox reactions is a promising route for opening novel synthetic pathways, and catalytic approaches to complex formation are critical for facilitating this chemistry. This report describes the use of a substituted hydroquinone catalyst to promote radical perfluoroalkylation reactions. Mechanistic studies indicate that the reaction is initiated through formation of a visible light-absorbing halogen bonding complex between the hydroquinone catalyst and the perfluoroalkyl halide radical precursor.

Direct amidation of acid fluorides using germanium amides.

Amide functional groups are an essential linkage that are found in peptides, proteins, and pharmaceuticals and new methods are constantly being sought for their formation. Here, a new method for their preparation is presented where germanium amides Ph3GeNR2 convert acid fluorides directly to amides. These germanium amides serve to abstract the fluorine atom of the acid fluoride and transfer their amide group -NR2 to the carbonyl carbon, and so function as amidation reagents.

Interactive Molecular Model Assembly with 3D Printing.

With the growth in accessibility of 3D printing, there has been a growing application of and interest in additive manufacturing processes in chemical laboratories and chemical education. Building on the long and successful history of physical modeling of molecular systems, we present select models along with a protocol to facilitate 3D printing of molecular structures that are able to do more than represent shape and connectivity. Models assembled as described incorporate dynamic aspects and degrees of freedom into saturated hydrocarbon structures. As a representative example, cyclohexane was assembled from parts printed and finished using different thermoplastics, and the resulting models retain their functionality at a variety of scales. The resulting structures show configurational space accessibility consistent with calculations and literature, and versions of these structures can be used as aids to illustrate concepts that are difficult to convey in other ways. This exercise enables us to evaluate successful printing protocols, make practical recommendations for assembly, and outline design principles for physical modeling of molecular systems. The provided structures, procedures, and results provide a foundation for individual manufacture and exploration of molecular structure and dynamics with 3D printing.

Computational Signaling Protein Dynamics and Geometric Mass Relations in Biomolecular Diffusion.

We present an atomistic level computational investigation of the dynamics of a signaling protein, monocyte chemoattractant protein-1 (MCP-1), that explores how simulation geometry and solution ionic strength affect the calculated diffusion coefficient. Using a simple extension of noncubic finite size diffusion correction expressions, it is possible to calculate experimentally comparable diffusion coefficients that are fully consistent with those determined from cubic box simulations. Additionally, increasing the concentration of salt in the solvent environment leads to changes in protein dynamics that are not explainable through changes in solvent viscosity alone. This work in accurate computational determination of protein diffusion coefficients led us to investigate molecular-weight-based predictors for biomolecular diffusion. By introducing protein volume- and protein surface-area-based extensions of traditional statistical relations connecting particle molecular weight to diffusion, we find that protein solvent-excluded surface area rather than volume works as a better geometric property for estimating biomolecule Stokes radii. This work highlights the considerations necessary for accurate computational determination of biomolecule diffusivity and presents insight into molecular weight relations for diffusion that could lead to new routes for estimating protein diffusion beyond the traditional approaches.

How Water's Properties Are Encoded in Its Molecular Structure and Energies.

How are water's material properties encoded within the structure of the water molecule? This is pertinent to understanding Earth's living systems, its materials, its geochemistry and geophysics, and a broad spectrum of its industrial chemistry. Water has distinctive liquid and solid properties: It is highly cohesive. It has volumetric anomalies-water's solid (ice) floats on its liquid; pressure can melt the solid rather than freezing the liquid; heating can shrink the liquid. It has more solid phases than other materials. Its supercooled liquid has divergent thermodynamic response functions. Its glassy state is neither fragile nor strong. Its component ions-hydroxide and protons-diffuse much faster than other ions. Aqueous solvation of ions or oils entails large entropies and heat capacities. We review how these properties are encoded within water's molecular structure and energies, as understood from theories, simulations, and experiments. Like simpler liquids, water molecules are nearly spherical and interact with each other through van der Waals forces. Unlike simpler liquids, water's orientation-dependent hydrogen bonding leads to open tetrahedral cage-like structuring that contributes to its remarkable volumetric and thermal properties.

Adapting the semi-explicit assembly solvation model for estimating water-cyclohexane partitioning with the SAMPL5 molecules.

We describe here some tests we made in the SAMPL5 communal event of 'Semi-Explicit Assembly' (SEA), a recent method for computing solvation free energies. We combined the prospective tests of SAMPL5 with followup retrospective calculations, to improve two technical aspects of the field variant of SEA. First, SEA uses an approximate analytical surface around the solute on which a water potential is computed. We have improved and simplified the mathematical model of that surface. Second, some of the solutes in SAMPL5 were large enough to need a way to treat solvating waters interacting with 'buried atoms', i.e. interior atoms of the solute. We improved SEA with a buried-atom correction. We also compare SEA to Thermodynamic Integration molecular dynamics simulations, so that we can sort out force field errors.

Predicting water-to-cyclohexane partitioning of the SAMPL5 molecules using dielectric balancing of force fields.

Alchemical transformation of solutes using classical fixed-charge force fields is a popular strategy for assessing the free energy of transfer in different environments. Accurate estimations of transfer between phases with significantly different polarities can be difficult because of the static nature of the force fields. Here, we report on an application of such calculations in the SAMPL5 experiment that also involves an effort in balancing solute and solvent interactions via their expected static dielectric constants. This strategy performs well with respect to predictive accuracy and correlation with unknown experimental values. We follow this by performing a series of retrospective investigations which highlight the potential importance of proper balancing in these systems, and we use a null hypothesis analysis to explore potential biases in the comparisons with experiment. The collective findings indicate that considerations of force field compatibility through dielectric behavior is a potential strategy for future improvements in transfer processes between disparate environments.

Small molecule solvation changes due to the presence of salt are governed by the cost of solvent cavity formation and dispersion.

We are interested in the free energies of transferring nonpolar solutes into aqueous NaCl solutions with salt concentrations upwards of 2 M, the Hofmeister regime. We use the semi-explicit assembly (SEA) computational model to represent these electrolyte solutions. We find good agreement with experiments (Setschenow coefficients) on 43 nonpolar and polar solutes and with TIP3P explicit-solvent simulations. Besides being much faster than explicit solvent calculations, SEA is more accurate than the PB models we tested, successfully capturing even subtle salt effects in both the polar and nonpolar components of solvation. We find that the salt effects are mainly due to changes in the cost of forming nonpolar cavities in aqueous NaCl solutions, and not mainly due to solute-ion electrostatic interactions.

TRIFORCE: Tessellated Semianalytical Solvent Exposed Surface Areas and Derivatives.

We present a new approach to the calculation of solvent-accessible surface areas of molecules with potential application to surface area based methods for determination of solvation free energies. As in traditional analytical and statistical approaches, this new algorithm, called TRIFORCE, reports both component areas and derivatives as a function of the atomic coordinates and radii. Unique to TRIFORCE are the rapid and scalable approaches for the determination of sphere intersection points and numerical estimation of the surface areas, derivatives, and other properties that can be associated with the surface area facets. The algorithm performs a special tessellation and semianalytical integration that uses a precomputed look-up table. This provides a simple way to balance numerical accuracy and memory usage. TRIFORCE calculates derivatives in the same manner, enabling application in force-dependent activities such as molecular geometry minimization. TRIFORCE is available free of charge for academic purposes as both a C++ library, which can be directly interfaced to existing molecular simulation packages, and a web-accessible application.

A fixed-charge model for alcohol polarization in the condensed phase, and its role in small molecule hydration.

We present a simple optimization strategy for incorporating experimental dielectric response information on neat liquids in classical molecular models of alcohol. Using this strategy, we determine simple and transferable hydroxyl modulation rules that, when applied to an existing molecular parameter set, result in a newly dielectric corrected (DC) parameter set. We applied these rules to the general Amber force field (GAFF) to form an initial set of GAFF-DC parameters, and we found this to lead to significant improvement in the calculated dielectric constant and hydration free energy values for a wide variety of small molecule alcohol models. Tests of the GAFF-DC parameters in the SAMPL4 blind prediction event for hydration show these changes improve agreement with experiment. Surprisingly, these simple modifications also outperform detailed quantum mechanical electric field calculations using a self-consistent reaction field environment coupling term. This work provides a potential benchmark for future developments in methods for representing condensed-phase environments in electronic structure calculations.

Using interpolation for fast and accurate calculation of ion-ion interactions.

We perform extensive molecular dynamics (MD) simulations between pairs of ions of various diameters (2-5.5 Å in increments of 0.5 Å) and charge (+1 or -1) interacting in explicit water (TIP3P) under ambient conditions. We extract their potentials of mean force (PMFs). We develop an interpolation scheme, called i-PMF, that is capable of capturing the full set of PMFs for arbitrary combinations of ion sizes ranging from 2 to 5.5 Å. The advantage of the interpolation process is computational cost. Whereas it can take 100 h to simulate each PMF by MD, we can compute an equivalently accurate i-PMF in seconds. This process may be useful for rapid and accurate calculation of the strengths of salt bridges and the effects of bridging waters in biomolecular simulations. We also find that our data is consistent with Collins' "law of matching affinities" of ion solubilities: small-small or large-large ion pairs are poorly soluble in water, whereas small-large are highly soluble.

Testing the semi-explicit assembly model of aqueous solvation in the SAMPL4 challenge.

Here, we test a method, called semi-explicit assembly (SEA), that computes the solvation free energies of molecules in water in the SAMPL4 blind test challenge. SEA was developed with the intention of being as accurate as explicit-solvent models, but much faster to compute. It is accurate because it uses pre-simulations of simple spheres in explicit solvent to obtain structural and thermodynamic quantities, and it is fast because it parses solute free energies into regionally additive quantities. SAMPL4 provided us the opportunity to make new tests of SEA. Our tests here lead us to the following conclusions: (1) The newest version, called Field-SEA, which gives improved predictions for highly charged ions, is shown here to perform as well as the earlier versions (dipolar and quadrupolar SEA) on this broad blind SAMPL4 test set. (2) We find that both the past and present SEA models give solvation free energies that are as accurate as TIP3P. (3) Using a new approach for force field parameter optimization, we developed improved hydroxyl parameters that ensure consistency with neat-solvent dielectric constants, and found that they led to improved solvation free energies for hydroxyl-containing compounds in SAMPL4. We also learned that these hydroxyl parameters are not just fixing solvent exposed oxygens in a general sense, and therefore do not improve predictions for carbonyl or carboxylic-acid groups. Other such functional groups will need their own independent optimizations for potential improvements. Overall, these tests in SAMPL4 indicate that SEA is an accurate, general and fast new approach to computing solvation free energies.

Field-SEA: a model for computing the solvation free energies of nonpolar, polar, and charged solutes in water.

Previous work describes a computational solvation model called semi-explicit assembly (SEA). The SEA water model computes the free energies of solvation of nonpolar and polar solutes in water with good efficiency and accuracy. However, SEA gives systematic errors in the solvation free energies of ions and charged solutes. Here, we describe field-SEA, an improved treatment that gives accurate solvation free energies of charged solutes, including monatomic and polyatomic ions and model dipeptides, as well as nonpolar and polar molecules. Field-SEA is computationally inexpensive for a given solute because explicit-solvent model simulations are relegated to a precomputation step and because it represents solvating waters in terms of a solute's free-energy field. In essence, field-SEA approximates the physics of explicit-model simulations within a computationally efficient framework. A key finding is that an atom's solvation shell inherits characteristics of a neighboring atom, especially strongly charged neighbors. Field-SEA may be useful where there is a need for solvation free-energy computations that are faster than explicit-solvent simulations and more accurate than traditional implicit-solvent simulations for a wide range of solutes.

Simple liquid models with corrected dielectric constants.

Molecular simulations often use explicit-solvent models. Sometimes explicit-solvent models can give inaccurate values for basic liquid properties, such as the density, heat capacity, and permittivity, as well as inaccurate values for molecular transfer free energies. Such errors have motivated the development of more complex solvents, such as polarizable models. We describe an alternative here. We give new fixed-charge models of solvents for molecular simulations--water, carbon tetrachloride, chloroform, and dichloromethane. Normally, such solvent models are parametrized to agree with experimental values of the neat liquid density and enthalpy of vaporization. Here, in addition to those properties, our parameters are chosen to give the correct dielectric constant. We find that these new parametrizations also happen to give better values for other properties, such as the self-diffusion coefficient. We believe that parametrizing fixed-charge solvent models to fit experimental dielectric constants may provide better and more efficient ways to treat solvents in computer simulations.

A microscopic theory of solvation of monoions.

The solvation free energies of ions are often computed using continuum theories, like the Born model. The Born model has the disadvantages that to fit experimental data, ionic radii are taken as adjustable parameters and you need to know the dielectric constant. We present here a more microscopic treatment for computing the free energies of ion solvation in water. Like the Born model, it gives an expression that is simple and can be computed quickly, but unlike the Born model, it uses true ionic radii and does not require inputting a dielectric constant. We show that the present model gives predictions for the free energies of transfer of alkali and halide ions into water that are in excellent agreement with recent experimentally derived estimates.

Testing the semi-explicit assembly solvation model in the SAMPL3 community blind test.

We report here a test of the Semi-Explicit Assembly (SEA) model in the solvation free energy category of the SAMPL3 blind prediction event (summer 2011). We tested how dependent the SEA results are on the chosen force field by performing calculations with both the General Amber and OPLS force fields. We compared our SEA results with full molecular dynamics simulations in explicit solvent. Of the 20 submissions, our SEA/OPLS results gave the second smallest RMS errors in free energies compared to experiments. SEA gives results that are very similar to those of its underlying force field and explicit solvent model. Hence, while the SEA water modeling approach is much faster than explicit solvent simulations, its predictions appear to be just as accurate.

Modeling aqueous solvation with semi-explicit assembly.

We describe a computational solvation model called semi-explicit assembly (SEA). SEA water captures much of the physics of explicit-solvent models but with computational speeds approaching those of implicit-solvent models. We use an explicit-water model to precompute properties of water solvation shells around simple spheres, then assemble a solute's solvation shell by combining the shells of these spheres. SEA improves upon implicit-solvent models of solvation free energies by accounting for local solute curvature, accounting for near-neighbor nonadditivities, and treating water's dipole as being asymmetrical with respect to positive or negative solute charges. SEA does not involve parameter fitting, because parameters come from the given underlying explicit-solvation model. SEA is about as accurate as explicit simulations as shown by comparisons against four different homologous alkyl series, a set of 504 varied solutes, solutes taken retrospectively from two solvation-prediction events, and a hypothetical polar-solute series, and SEA is about 100-fold faster than Poisson-Boltzmann calculations.

Physical Modeling of Aqueous Solvation.

We consider the free energies of solvating molecules in water. Computational modeling usually involves either detailed explicit-solvent simulations, or faster computations, which are based on implicit continuum approximations or additivity assumptions. These simpler approaches often miss microscopic physical details and non-additivities present in experimental data. We review explicit-solvent modeling that identifies the physical bases for the errors in the simpler approaches. One problem is that water molecules that are shared between two substituent groups often behave differently than waters around each substituent individually. One manifestation of non-additivities is that solvation free energies in water can depend not only on surface area or volume, but on other properties, such as the surface curvature. We also describe a new computational approach, called Semi-Explicit Assembly, that aims to repair these flaws and capture more of the physics of explicit water models, but with computational efficiencies approaching those of implicit-solvent models.

Oil/water transfer is partly driven by molecular shape, not just size.

We present a new approach to computer modeling of solvation free energies of oil in water. In Semi-Explicit Assembly, we first precompute structural and thermal properties of TIP3P waters around different Lennard-Jones spheres. This tabulated information is then used to compute the nonpolar solvation properties of arbitrary solutes. By accumulating interactions from whole regions of the solute molecule, Semi-Explicit Assembly more properly accounts for effects of solute shape and solves problems that appear as nonadditivities in traditional gammaA approaches. Semi-Explicit Assembly involves little parameter fitting because the solute and water properties are taken from existing force fields. We tested the predictions on alkanes, alkynes, linear and planar polyaromatic hydrocarbons, and on a diverse set of 504 molecules previously explored by explicit solvent simulations. We found that not all hydrocarbons are the same. Hydrocarbons have "hot spots", places where first-shell waters interact more strongly with the molecule than at other locations. For example, waters are more attracted to hover over hydrocarbon rings than at the edges. By accounting for these collective regional effects, Semi-Explicit Assembly approaches the physical accuracies of explicit solvent models in computing nonpolar solvation free energies, but because of the precomputations and the regional additivities, it is nearly as fast to compute as gammaA methods.