The substantial increase in the number of active and inactive-state CB1 receptor experimental structures has provided opportunities for CB1 drug discovery using various structure-based drug design methods, including the popular end-point methods for predicting binding free energies-Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA). In this study, we have therefore evaluated the performance of MM/PBSA and MM/GBSA in calculating binding free energies for CB1 receptor. Additionally, with both MM/PBSA and MM/GBSA being known for their highly individualized performance, we have evaluated the effects of various simulation parameters including the use of energy minimized structures, choice of solute dielectric constant, inclusion of entropy, and the effects of the five GB models. Generally, MM/GBSA provided higher correlations than MM/PBSA (rMM/GBSA = 0.433 - 0.652 vs. rMM/PBSA = 0.100 - 0.486) regardless of the simulation parameters, while also offering faster calculations. Improved correlations were observed with the use of molecular dynamics ensembles compared with energyminimized structures and larger solute dielectric constants. Incorporation of entropic terms led to unfavorable results for both MM/PBSA and MM/GBSA for a majority of the dataset, while the evaluation of the various GB models exerted a varying effect on both the datasets. The findings obtained in this study demonstrate the utility of MM/PBSA and MM/GBSA in predicting binding free energies for the CB1 receptor, hence providing a useful benchmark for their applicability in the endocannabinoid system as well as other G protein-coupled receptors. The study utilized the docked dataset (Induced Fit Docking with Glide XP scoring function) from Loo et al., consisting of 46 ligands-23 agonists and 23 antagonists. The equilibrated structures from Loo et al. were subjected to 30ns production simulations using GROMACS 2018 at 300K and 1atm with the velocity rescaling thermostat and the Parinello-Rahman barostat. AMBER ff99SB*-ILDN was used for the proteins, General Amber Force Field (GAFF) was used for the ligands, and Slipids parameters were used for lipids. MM/PBSA and MM/GBSA binding free energies were then calculated using gmx_MMPBSA. The solute dielectric constant was varied between 1, 2, and 4 to study the effect of different solute dielectric constants on the performance of MM/PB(GB)SA. The effect of entropy on MM/PB(GB)SA binding free energies was evaluated using the interaction entropy module implemented in gmx_MMPBSA. Five GB models, GBHCT, GBOBC1, GBOBC2, GBNeck, and GBNeck2, were evaluated to study the effect of the choice of GB models in the performance of MM/GBSA. Pearson correlation coefficients were used to measure the correlation between experimental and predicted binding free energies.

We investigated the effective interaction potential (EIP) between charged surfaces in solvent comprised of dipole dimer molecules added with a certain amount of ionic liquid. Using classical density functional theory, the EIP is calculated and decoupled into entropic and energy terms. Unlike the traditional Asakura–Oosawa (AO) depletion model, the present entropic term can be positive or negative, depending on the entropy change associated with solvent molecule migration from bulk into slit pore. This is determined by pore congestion and disruption of the bulk dipole network. The energy term is determined by the free energy associated with hard-core repulsion and electrostatic interactions between surface charges, ion charges, and polarized charges carried by the dipole dimer molecules. The calculations in this article clearly demonstrate the variability of the entropy term, which contrasts sharply with the traditional AO depletion model, and the corrective effects of electrostatic and spatial hindrance interactions on the total EIP; we revealed several non-monotonic behaviors of the EIP and its entropic and energy terms concerning solvent bulk concentration and solvent molecule dipole moment; additionally, we demonstrated the promoting effect of dipolar solvent on the emergence of like-charge attraction, even in 1:1 electrolyte solutions. The microscopic origin of the aforementioned phenomena was analyzed to be due to the non-monotonic change of dipolar solvent adsorption with dipole moment under conditions of low solution dielectric constant. The present findings offer novel approaches and molecular-level guidance for regulating the EIP. This insight has implications for understanding fundamental processes in various fields, including biomolecule-ligand binding, activation energy barriers, ion tunneling transport, as well as the formation of hierarchical structures, such as mesophases, micro-, and nanostructures, and beyond.

Accurate calculation of the binding free energies between a protein and a ligand is the primary objective of structure-based drug design, but it still remains a challenging problem. In this work, we apply the screening molecular mechanics/Poisson Boltzmann surface area (MM/PBSA) method to calculate the binding affinity of protein-ligand interactions. Our results show that the performance of the screening MM/PBSA is better than that of the standard MM/PBSA, especially in a charged-ligand system. In addition, we also investigate the effect of the solute dielectric constant on the results, and find that the optimal solute dielectric constants are different between the neutral-ligand system and the charged-ligand system. Moreover, we also evaluate the effect of the atomic-charge methods on the performance of the screening MM/PBSA. The present study demonstrates that the screening MM/PBSA should be a reliable method for calculating binding energy of biosystems.

The effect of lithium salt concentration in an aprotic solvent on the oxygen reaction

Most multivalent secondary batteries have employed electrolytes composed of cyclic ether solvents such as tetrahydrofuran or linear glycol ether solvents (glymes) such as 1,2-dimethoxyethane (G1). A robust understanding of multivalent cation solvation tendencies in these classes of solvents provides insight into corresponding structure–property relationships which, in turn, promotes the design and discovery of improved electrolytes. In this work, our goal is to systematically address how electrolyte constituent properties, namely, ether solvent structure and dication size, direct the solvation interactions of divalent electrolytes and their resultant properties. This study utilizes pulsed-field gradient (PFG) nuclear magnetic resonance (NMR) spectroscopy in conjunction with Raman spectroscopy and ionic conductivity measurements to elucidate the preferential interactions between multivalent cations, anions, and solvent molecules along with their correlated ion dynamics. These investigations incorporate two representative divalent cations (Ca2+ and Zn2+) as well as two ethereal solvent representatives from both the cyclic ether and glyme structural classes. The results reveal that anions coordinate more readily with divalent cations in cyclic ethers than in glymes. Furthermore, the coordination of the anions with Ca2+, i.e., contact-ion pair (CIP) formation is more pronounced than with Zn2+ in a glyme solvent of limited chain length (G1), providing insight into cation size effects that are important for translating solvation behavior across various multivalent electrolytes. Importantly, we find that specific anion coordination is more strongly controlled by solvent structure than by salt concentration in the practical range of 0.1–0.5 M. However, simply reducing these inner-sphere inter-ionic interactions by changing solvent structure does not necessarily de-correlate ionic motion. Instead, concentration-dependent changes in molar ionic conductivity suggest that second-shell interactions, i.e., solvent separated ion pairs (SSIPs), are prevalent in these electrolytes and that the solution dielectric constant, which is increased by the presence of dipolar ion pairs, is critical for controlling these interactions. These findings thus provide a basis for understanding the physical chemistry of multivalent battery electrolytes.

Classically, stable covalent bonding cannot occur between heavy metal cations and clay surface O atoms. However, the classical theory ignores the effect of the electric field arising from clay surface charges on the orbitals of surface O atoms. This article studies the adsorption behavior of heavy metal cations (Pb2+, Cd2+, Cu2+, and Zn2+) on charged montmorillonite surfaces from a new theoretical foundation based on the quantum mechanics analysis of surface O atoms in this electric field, which reveals that polarization-induced covalent bonding is a strong adsorption force. The strength of polarization-induced covalent bonding can be controlled by regulating the energy of the lone-pair electrons of surface O atoms, which depends on solution pH, electrolyte type, electrolyte concentration, temperature or dielectric constant of medium, etc. The mathematic relationship between the energy of lone-pair electrons of surface O atoms and electric field arising from surface charges was established through quantum mechanics analysis; and correspondingly the mathematical relationship between the polarization-induced covalent bonding energy and surface potential also was established for different heavy metal cations. The finding of the new adsorption force will have important impact on both theoretical research and removal/deactivation approaches of heavy metal cations.

Predicting the interactions between a set of small molecules and its target plays a critical role in drug discovery and development. Especially in later stages of the drug design process, when a reduced set of molecules is in focus, reliable and accurate binding affinity estimations are important for targeted modifications of given lead molecules.Current limitations in affinity prediction originate from the lack of accurate estimates for solvation energy and entropy. MM-PBSA and the related MM-GBSA aim at providing better estimates.From our studies we infer that the common approach using one dielectric constant for the binding pocket may be misleading (here in the case of a kinase), especially when designed ligands/drugs contain charges. Thus, a range of selected values for the solute dielectric constant is preferred for better and more reliable comparisons.

In structure-based drug design (SBDD), the molecular mechanics generalized Born surface area (MM/GBSA) approach has been widely used in ranking the binding affinity of small molecule ligands. However, an accurate estimation of protein-ligand binding affinity still remains a challenge due to the intrinsic limitation of the standard generalized Born (GB) model used in MM/GBSA. In this study, we proposed and evaluated the MM/GBSA approach based on a variable dielectric generalized Born (VDGB) model using residue-type-based dielectric constants. In the VDGB model, different dielectric values were assigned for the three types of protein residues, and the magnitude of the dielectric constants for residue types follows this order: charged ≥ polar ≥ nonpolar. We found that MM/GBSA based on a VDGB model (MM/GBSAVDGB) with an optimal dielectric constant of 4.0 for the charged residues and 1.0 for the noncharged residues together with a net-charge-dependent dielectric value for ligands achieved better predictions as judged by Pearson's correlation coefficient than the standard MM/GBSA with a uniform solute dielectric constant of 4.0 for the training set of 130 protein-ligand complexes. The prediction on the test set with 165 protein-ligand complexes also validated the better performance of MM/GBSAVDGB. Moreover, this method exhibited potential in predicting the relative binding free energies for multiple ligands against the same target. Furthermore, we found that rational truncation of protein residues far from the binding site can significantly speed up the MM/GBSAVDGB calculations, while it almost does not influence the prediction accuracy. Therefore, it is feasible to implement the system-truncated MM/GBSAVDGB as a scoring function for SBDD.

Folding and structural polymorphism of p53 C-terminal domain: One peptide with many conformations

With the potential of improving virtual screening outcome, MM-PB/GBSA has become a disputed method that requires extensive testing and tuning to provide the optimal results. One of the tuning factors is the internal or solute dielectric constant. We have applied three test sets with receptors of different categories and libraries from different sources to investigate the underlying issue related to this constant. We discovered that increasing internal dielectric value does not improve the virtual screening enrichment qualitatively. More interestingly, nonpolar and polar calculated energies act differently in libraries with different molecular weight distributions. From this work, the performance of MM-PBSA rescoring in virtual screening is more library- than receptor-dependent.

Exploring the Structural Properties of Synaptotagmin's Intrinsically Disordered Region

Many cells synthesize significant quantities of zwitterionic osmolytes to cope with the osmotic stress induced by excess salt. In addition to their primary role in balancing osmotic pressure, these osmolytes also help stabilize protein structure and restore enzymatic activity compromised by high ionic strength. This osmoprotective effect has been studied extensively, but its electrostatic aspects have somehow escaped the mainstream. Here, we report that, despite their overall neutrality, zwitterions may dramatically affect electrostatic interactions in saline solutions of biological relevance. Using atomic force microscopy, we study the combined effect of osmolytes and salts on electrostatic interactions between two negatively charged silica surfaces in mixtures of five salts (NaCl, KCl, CsCl, MgCl2, and CaCl2) and five zwitterionic osmolytes (betaine, proline, trimethylamine N-oxide, glycine, and sarcosine) as a function of solutes concentration and pH. All osmolytes are found to counteract the screening effect of salt on electrostatic repulsion, albeit to a different extent. They do so by both increasing the screening length shortened by added salts and by desorbing bound protons and cations, hence enhancing the negative surface charge. Both effects are traced to the osmolytes' higher molecular polarizability compared with water. In addition to this direct effect on the solution's dielectric constant, we identify an osmolytic Hofmeister effect with the more hydrophobic osmolytes more efficiently desorbing weakly hydrated cations from weakly hydrated silica and the less hydrophobic osmolytes better desorbing strongly hydrated cations from strongly hydrated silica. The combined results shed light on Coulomb interactions in a more realistic model of the cytosol, a relatively unexplored territory.

Block copolymer-assisted synthesis of monodisperse colloidal patchy nanoparticles

ABSTRACTThis paper reports a new method of detecting the concentration (mol L−1) of methanol by the use of a two-dimensional photonic crystal slab. Photonic band gap parameters are calculated using the plane wave expansion method. To find a model which has higher accuracy and practicality or applicability, fill factors used to analyze and compare the properties of the slab were computed. There is a linear proportional relationship between photonic band gap and dielectric constant of solution, which can be utilized to measure the concentration of methanol. The start frequency and the cutoff frequency also have a linear relationship with the dielectric constant of solution. The results show that a honeycomb lattice structure possesses better self-test functionality.

In this study, a predictive model is presented for estimation of second order thermodynamic properties of electrolyte solutions. In order to provide a comprehensive understanding, the capability of modified electrolyte PC‐SAFT up to high pressure and temperature has been studied. In addition to the first order derivative thermodynamic properties, the Gibbs free energy, enthalpy and heat capacity of aqueous electrolyte solutions at infinite dilution are predicted. Using new methodology, the dielectric constant is modified to keep the pressure, temperature, and ionic strength dependency. Our results show that the Born term has a significant contribution on prediction of second order derivative properties. Meanwhile the impact of temperature‐dependent solution dielectric constant on standard state heat capacity is studied. Finally, the isobaric heat capacity at various salt concentrations is predicted without any adjustable parameters. The results of this work indicate an acceptable agreement with experimental data especially at high pressure and temperature. © 2017 American Institute of Chemical Engineers AIChE J, 2017

We address the possible occurrence of a minimum extent of dissociation (α) of ionic liquid (IL) in IL-solvent mixtures. This phenomenon, known as the redissociation of IL, is responsible for many interesting composition-dependent properties in such mixtures. A thermodynamic model is developed to provide a semiquantitative prediction on the change of α with solvent concentration. It is found that the occurrence of minimum α coincides with the occurrence of a maximum in the mean activity coefficient of dissociated ions, indicating better solvation of free, dissociated ions both with decreasing and increasing solvent concentration. The favorable solvation of free ions is found to change from long-range ion-solvent dielectric polarization to ion-ion-pair dielectric polarization with decreasing solvent concentration. Therefore, the composition dependence of the IL solution dielectric constants, determined from that of the ion-pair and the solvent, is found to be the most important factor for the presence of redissociation in IL solutions.

Microwave dielectric properties and electrical conductivity were studied in aqueous solutions along the section of the Y(HCOO)3–Ba(НСОО)2–Cu(HCOO)2–H2O quaternary system where the total salt concentration is from 0.3 to 18.9 mol % (the salt component ratio is 1: 2: 3). Thereby, unsaturated, saturated, and supersaturated solutions were included into the description. The measurements were performed at 298 K at frequencies of 13, 16, 19, and 25 GHz. Static dielectric permittivities (dielectric constants) and dielectric relaxation times, the key parameters of state of water molecules, were calculated. At the concentrations where the initial water structure is nonexistent and the dielectric constants of solutions have low values, water molecules have slowed dynamics and complex ion–water species are formed. The appearance of these species determines the formation of metastable solutions and glassy phases. This makes it possible to manufacture homogeneous multicomponent water–salt compositions in solid state to be used as precursors for the production of oxide materials.

The location of the hydroxyl group in monohydroxy alcohols greatly affects the temperature dependence of the liquid structure due to hydrogen bonding. Temperature-dependent self-diffusion coefficients, fluidity (the inverse of viscosity), dielectric constant, and density have been measured for several 1-alcohols and 3-alcohols with varying alkyl chain lengths. The data are modeled using the compensated Arrhenius formalism (CAF). The CAF follows a modified transition state theory using an Arrhenius-like expression to describe the transport property, which consists of a Boltzmann factor containing an energy of activation, Ea, and an exponential prefactor containing the temperature-dependent solution dielectric constant, εs(T). Both 1- and 3-alcohols show the Ea of diffusion coefficients (approximately 43 kJ mol(-1)) is higher than the Ea of fluidity (approximately 35 kJ mol(-1)). The temperature dependence of the exponential prefactor in these associated liquids is explained using the dielectric constant and the Kirkwood-Frölich correlation factor, gk. It is argued that the dielectric constant must be used to account for the additional temperature dependence due to variations in the liquid structure (e.g., hydrogen bonding) for the CAF to accurately model the transport property.

Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) methods have become widely adopted in estimating protein-ligand binding affinities due to their efficiency and high correlation with experiment. Here different computational alternatives were investigated to assess their impact to the agreement of MMPBSA calculations with experiment. Seven receptor families with both high-quality crystal structures and binding affinities were selected. First the performance of nonpolar solvation models was studied and it was found that the modern approach that separately models hydrophobic and dispersion interactions dramatically reduces RMSD's of computed relative binding affinities. The numerical setup of the Poisson-Boltzmann methods was analyzed next. The data shows that the impact of grid spacing to the quality of MMPBSA calculations is small: the numerical error at the grid spacing of 0.5 Å is already small enough to be negligible. The impact of different atomic radius sets and different molecular surface definitions was further analyzed and weak influences were found on the agreement with experiment. The influence of solute dielectric constant was also analyzed: a higher dielectric constant generally improves the overall agreement with experiment, especially for highly charged binding pockets. The data also showed that the converged simulations caused slight reduction in the agreement with experiment. Finally the direction of estimating absolute binding free energies was briefly explored. Upon correction of the binding-induced rearrangement free energy and the binding entropy lost, the errors in absolute binding affinities were also reduced dramatically when the modern nonpolar solvent model was used, although further developments were apparently necessary to further improve the MMPBSA methods. © 2016 Wiley Periodicals, Inc.

We propose an analytic approach for calculating the electrostatic energy of proteins or protein complexes in aqueous solution. This method, termed CVCEL (Circular Variance Continuum ELectrostatics), is fitted to Poisson calculations and is able to reproduce the corresponding energies for different choices of solute dielectric constant. CVCEL thus treats both solute charge interactions and charge self-energies, and it can also deal with salt solutions. Electrostatic damping notably depends on the degree of solvent exposure of the charges, quantified here in terms of circular variance, a measure that reflects the vectorial distribution of the neighbors around a given center. CVCEL energies can be calculated rapidly and have simple analytical derivatives. This approach avoids the need for calculating effective atomic volumes or Born radii. After describing how the method was developed, we present test results for coarse-grain proteins of different shapes and sizes, using different internal dielectric constants and different salt concentrations and also compare the results with those from simple distance-dependent models. We also show that the CVCEL approach can be used successfully to calculate the changes in electrostatic energy associated with changes in protein conformation or with protein-protein binding.