Continuum Solvation Methods Research Articles

Crystal Polymorph Search in the NPT Ensemble via a Deposition/Sublimation Alchemical Path.

The formulation of active pharmaceutical ingredients involves discovering stable crystal packing arrangements or polymorphs, each of which has distinct pharmaceutically relevant properties. Traditional experimental screening techniques utilizing various conditions are commonly supplemented with in silico crystal structure prediction (CSP) to inform the crystallization process and mitigate risk. Predictions are often based on advanced classical force fields or quantum mechanical calculations that model the crystal potential energy landscape but do not fully incorporate temperature, pressure, or solution conditions during the search procedure. This study proposes an innovative alchemical path that utilizes an advanced polarizable atomic multipole force field to predict crystal structures based on direct sampling of the NPT ensemble. The use of alchemical (i.e., nonphysical) intermediates, a novel Monte Carlo barostat, and an orthogonal space tempering bias combine to enhance the sampling efficiency of the deposition/sublimation phase transition. The proposed algorithm was applied to 2-((4-(2-(3,4-dichlorophenyl)ethyl)phenyl)amino)benzoic acid (Cambridge Crystallography Database Centre ID: XAFPAY) as a case study to showcase the algorithm. Each experimentally determined polymorph with one molecule in the asymmetric unit was successfully reproduced via approximately 1000 short 1 ns simulations per space group where each simulation was initiated from random rigid body coordinates and unit cell parameters. Utilizing two threads of a recent Intel CPU (a Xeon Gold 6330 CPU at 2.00 GHz), 1 ns of sampling using the polarizable AMOEBA force field can be acquired in 4 h (equating to more than 300 ns/day using all 112 threads/56 cores of a dual CPU node) within the Force Field X software (https://ffx.biochem.uiowa.edu). These results demonstrate a step forward in the rigorous use of the NPT ensemble during the CSP search process and open the door to future algorithms that incorporate solution conditions using continuum solvation methods.

Hydration numbers of biologically relevant divalent metal cations from abinitio molecular dynamics and continuum solvation methods.

Hydration and, in particular, the coordination number of a metal ion is of paramount importance as it defines many of its (bio)physicochemical properties. It is not only essential for understanding its behavior in aqueous solutions but also determines the metal ion reference state and its binding energy to (bio)molecules. In this paper, for divalent metal cations Ca2+, Cd2+, Cu2+, Fe2+, Hg2+, Mg2+, Ni2+, Pb2+, and Zn2+, we compare two approaches for predicting hydration numbers: (1) a mixed explicit/continuum DFT-D3//COSMO-RS solvation model and (2) density functional theory based abinitio molecular dynamics. The former approach is employed to calculate the Gibbs free energy change for the sequential hydration reactions, starting from [M(H2O)2]2+ aqua complexes to [M(H2O)9]2+, allowing explicit water molecules to bind in the first or second coordination sphere and determining the most stable [M(H2O)n]2+ structure. In the latter approach, the hydration number is obtained by integrating the ion-water radial distribution function. With a couple of exceptions, the metal ion hydration numbers predicted by the two approaches are in mutual agreement, as well as in agreement with the experimental data.

Identification of potential drug molecules against fibroblast growth factor receptor 3 (FGFR3) by multi-stage computational-biophysics correlate

The fibroblast growth factor receptor 3 (FGFR3) is warranted as a promising therapeutic target in bladder cancer as it is described in 75% of papillary bladder tumors. Considering this, the present study was conducted to use different approaches of computer-aided drug discovery (CADD) to identify the best binding compounds against the active pocket of FGFR3. Compared to control pyrimidine derivative, the study identified three promising lead structures; BDC_24037121, BDC_21200852, and BDC_21206757 with binding energy value of −14.80 kcal/mol, −12.22 kcal/mol, and −11.67 kcal/mol, respectively. The control molecule binding energy score was −9.85 kcal/mol. The compounds achieved deep pocket binding and produced balanced interactions of hydrogen bonds and van der Waals. The FGFR3 enzyme residues such as Leu478, Lys508, Glu556, Asn562, Asn622, and Asp635. The molecular dynamic (MD) simulation studies additionally validated the docked conformation stability with respect to FGFR3 with a mean root mean square deviation (RMSD) value of < 3 Å. The root mean square fluctuation (RMSF) complements the complexes structural stability and the residues showed less fluctuation in the presence of compounds. The Poisson–Boltzmann or generalized Born and surface area continuum solvation (MM/PBSA and MM/GBSA) methods revalidated compounds better binding and highlighted van der Waals energy to dominate the overall net energy. The docked stability was additionally confirmed by WaterSwap and AMBER normal mode entropy energy analyses. In a nutshell, the compounds shortlisted in this study are promising in term of theoretical binding affinity for FGFR3 but experimental validation is needed.Communicated by Ramaswamy H. Sarma

Building polarization into protein-inhibitor binding dynamics in rational drug design for rheumatoid arthritis

Standard force field-based simulations to accomplish structure-based evaluations of lead molecules is a powerful tool. Combining protein fragmentation into tractable sub-systems with continuum solvation method is envisaged to enable quantum mechanics-based electronic structure calculations of macromolecules in their realistic environment. This along with incorporation of many-body polarization effect in molecular dynamics simulations may augment an accurate description of electrostatics of protein-inhibitor systems for effective drug design. Rheumatoid arthritis (RA) is a complex autoimmune disorder plagued by the ceiling effect of current targeted therapies, encouraging identification of new druggable targets and corresponding drug design to tackle the refractory form of disease. In this study, polarization-inclusive force field approach has been used to model protein solvation and ligand binding for ‘Mitogen-activated protein kinase’ (MAP3K8), a regulatory node of notable pharmacological relevance in RA synovial biology. For MAP3K8 inhibitors belonging to different scaffold series, the calculations illustrated differential electrostatic contribution to their relative binding affinities and successfully explained examples from available structure-activity relationship studies. Results from this study exemplified i) the advantage of this approach in reliably ranking inhibitors having close nanomolar range activities for the same target; and ii) its prospective application in lead molecule identification aiding drug discovery efforts in RA. Communicated by Ramaswamy H. Sarma

A computational quest for identifying potential vaccine candidates against Moraxella lacunata: a multi-pronged approach

Moraxella lacunata is an emerging gram-negative bacterium that is responsible for multiple nosocomial infections. The bacterium is evolving resistance to several antibiotics, and currently, no effective licensed vaccines are available, which warrants the search for new therapeutics. A multi-epitope-based vaccine has been designed for M. lacunata. The complete proteome of M. lacunata contains 10,110 core proteins. Subcellular localization analysis revealed the presence of five proteins in the extracellular matrix, while 19 proteins were predicted to be located in the outer membrane, and 21 proteins were predicted to be located in the periplasmic region. Only two proteins, the type VI secretion system tube protein (Hcp) and the transporter substrate-binding domain-containing protein, were selected for epitope prediction as they fulfilled all the criteria for being potential vaccine candidates. Shortlisted epitopes from the selected proteins were fused together using “GPGPG” linkers to overcome the limitations of single-epitope vaccines. Next, the cholera toxin-B adjuvant was attached to the peptide epitope using an EAAAK linker. Docking analysis was performed to examine the interaction between the vaccine and immune cell receptors, revealing robust intermolecular interactions and a stable binding conformation. Molecular dynamics simulation findings revealed no drastic changes in the binding conformation of complexes during the simulation period. The net binding free energy of vaccine-receptor complexes was estimated using the molecular mechanics energies combined with the Poisson–Boltzmann and surface area continuum solvation (MM-PBSA) method. The reported values were −586.38 kcal/mol, −283.74 kcal/mol, and −296.88 kcal/mol for the TLR-4-vaccine complex, MHC-I-vaccine complex, and MHC-II-vaccine complex, respectively. Furthermore, the molecular mechanics energies combined with the generalized Born and surface area continuum solvation (MM-GBSA) analysis predicted binding free energies of −596.69 kcal/mol, −287.39 kcal/mol, and −298.28 kcal/mol for the TLR-4-vaccine complex, MHC-I-vaccine complex, and MHC-II-vaccine complex, respectively. The theoretical vaccine design proposed in the study could potentially serve as a powerful therapeutic against targeted pathogens, subject to validation through experimental studies. Communicated by Ramaswamy H. Sarma

Development and test of highly accurate endpoint free energy methods. 1: Evaluation of ABCG2 charge model on solvation free energy prediction and optimization of atom radii suitable for more accurate solvationfreeenergy prediction by the PBSA method.

Accurate estimation of solvation free energy (SFE) lays the foundation for accurate prediction of binding free energy. The Poisson-Boltzmann (PB) or generalized Born (GB) combined with surface area (SA) continuum solvation method (PBSA and GBSA) have been widely used in SFE calculations because they can achieve good balance between accuracy and efficiency. However, the accuracy of these methods can be affected by several factors such as the charge models, polar and nonpolar SFE calculation methods and the atom radii used in the calculation. In this work, the performance of the ABCG2 (AM1-BCC-GAFF2) charge model as well as other two charge models, that is, RESP (Restrained Electrostatic Potential) and AM1-BCC (Austin Model 1-bond charge corrections), on the SFE prediction of 544 small molecules in water by PBSA/GBSA was evaluated. In order to improve the performance of the PBSA prediction based on the ABCG2 charge, we further explored the influence of atom radii on the prediction accuracy and yielded a set of atom radius parameters for more accurate SFE prediction using PBSA based on the ABCG2/GAFF2 by reproducing the thermodynamic integration (TI) calculation results. The PB radius parameters of carbon, oxygen, sulfur, phosphorus, chloride, bromide and iodine, were adjusted. New atom types, on, oi, hn1, hn2, hn3, were introduced to further improve the fitting performance. Then, we tuned the parameters in the nonpolar SFE model using the experimental SFE data and the PB calculation results. By adopting the new radius parameters and new nonpolar SFE model, the root mean square error (RMSE) of the SFE calculation for the 544 molecules decreased from 2.38 to 1.05 kcal/mol. Finally, the new radius parameters were applied in the prediction of protein-ligand binding free energies using the MM-PBSA method. For the eight systems tested, we could observe higher correlation between the experiment data and calculation results and smaller prediction errors for the absolute binding free energies, demonstrating that our new radius parameters can improve the free energy calculation using the MM-PBSA method.

Reliable gas-phase tautomer equilibria of drug-like molecule scaffolds and the issue of continuum solvation.

Accurate calculation of relative tautomer energies in different environments is a prerequisite to many parameters of relevance in drug discovery. This work provides a thorough benchmark of the semiempirical methods AM1, PM3 and GFN2-xTB, the force-field OPLS4, Hartree-Fock and HF-3c, the density functionals PBEh-3c, B97-3c, r2SCAN-3c, PBE, PBE0, TPSS, r2SCAN, ω-B97X-V, M06-2X, B3LYP, B2PLYP, and second-order perturbation theory MP2 versus the gold-standard coupled-cluster DLPNO-CCSD(T) using the def2-QZVPP basis set. The outperforming method identified is M06-2X, whereas r2SCAN-3c is the best-perfoming one in the set of cost-optimized methods. Application of the two methods on a challenging subset from the SAMPL2 challenge provides evidence that deviations from experiment are caused by deficiencies of current continuum solvation methods.

(+)-Usnic acid and its salts, inhibitors of SARS‐CoV‐2, identified by using in silico methods and in vitro assay

The pandemic caused by severe acute respiratory Coronavirus-2 (SARS-CoV-2) has been ongoing for over two years, and treatment for COVID-19, other than monoclonal antibodies, is urgently required. Accordingly, we have investigated the inhibitors of SARS-CoV-2 protein targets by high-throughput virtual screening using a marine natural products database. Considering the calculated molecular properties and availability of the compounds, (+)-usnic acid was selected as a suitable hit. In the in vitro antiviral assay of (+)-usnic acid by the immunofluorescence method, IC50 was 7.99 μM, which is similar to that of remdesivir used as a positive control. The generalized Born and surface area continuum solvation (MM/GBSA) method was performed to find the potent target of (+)-usnic acid, and the Mpro protein showed the most prominent value, −52.05 kcal/mol, among other SARS-CoV-2 protein targets. Thereafter, RMSD and protein–ligand interactions were profiled using molecular dynamics (MD) simulations. Sodium usnate (NaU) improved in vitro assay results with an IC50 of 5.33 μM and a selectivity index (SI) of 9.38. Additionally, when (+)-usnic acid was assayed against SARS-CoV-2 variants, it showed enhanced efficacy toward beta variants with an IC50 of 2.92 μM and SI of 11.1. We report the in vitro anti-SARS-CoV-2 efficacy of (+)-usnic acid in this study and propose that it has the potential to be developed as a COVID-19 treatment if its in vivo efficacy has been confirmed.

Interaction of Pelargonium sidoides Compounds with Lactoferrin and SARS-CoV-2: Insights from Molecular Simulations.

(1) Background: Pelargonium sidoides extracts and lactoferrin are two important natural, anti-inflammatory, and antiviral agents, which can interfere with the early stages of SARS-CoV-2 infection. Molecular docking and molecular dynamics simulation approaches have been applied to check for the occurrence of interactions of the Pelargonium sidoides compounds with lactoferrin and with SARS-CoV-2 components. (2) Methods: Computational methods have been applied to confirm the hypothesis of a direct interaction between PEL compounds and the lactoferrin protein and between Pelargonium sidoides compounds and SARS-CoV-2 Spike, 3CLPro, RdRp proteins, and membrane. Selected high-score complexes were structurally investigated through classical molecular dynamics simulation, while the interaction energies were evaluated using the molecular mechanics energies combined with generalized Born and surface area continuum solvation method. (3) Results: Computational analyses suggested that Pelargonium sidoides extracts can interact with lactoferrin without altering its structural and dynamical properties. Furthermore, Pelargonium sidoides compounds should have the ability to interfere with the Spike glycoprotein, the 3CLPro, and the lipid membrane, probably affecting the functional properties of the proteins inserted in the double layer. (4) Conclusion: Our findings suggest that Pelargonium sidoides may interfere with the mechanism of infection of SARS-CoV-2, especially in the early stages.

Importance of Three-Body Problems and Protein–Protein Interactions in Proteolysis-Targeting Chimera Modeling: Insights from Molecular Dynamics Simulations

Proteolysis-targeting chimeras (PROTACs) are a class of bifunctional molecules that can induce the ubiquitin degradation of its target protein by hijacking the E3 ligase to form a target protein-PROTAC-E3 ligase ternary complex. Its underlying principle has inspired the development of a wide range of protein degraders that are similar to or beyond PROTACs in recent years. The formation of the ternary complexes is the key to the success of PROTAC-induced protein degradation. Nevertheless, the lack of effective ternary complex modeling techniques has limited the application of computer-aided drug discovery tools to this emerging and fast developing new land in drug industry. Thus, in this study, we explored the application of the more physically sound molecular dynamics simulation and the molecular mechanics combined with the generalized Born and surface area continuum solvation (MM/GBSA) method to solve the underlying three-body problem in PROTAC modeling. We first verified the accuracy of our approach using a series of known Brd4 BD2 degraders. The calculated binding energy showed a good correlation with the experimental Kd values. The modeling of a unique property, namely, the α value, for PROTACs was also first and accurately performed to our best knowledge. The results also demonstrated the importance of PROTAC-induced protein-protein interactions in its modeling, either qualitatively or quantitatively. Finally, by standing on the success of earlier docking-based approaches, our protocol was also applied as a rescoring function in pose prediction. The results showed a notable improvement in reranking the initial poses generated from a modified Rosetta method, which was reportedly one of the best among a handful of PROTAC modeling approaches available in this field. We hope this work could provide a practical protocol and more insights to study the binding and the design of PROTACs and other protein degraders.

Fragment-Based Ligand Discovery Applied to the Mycolic Acid Methyltransferase Hma (MmaA4) from Mycobacterium tuberculosis: A Crystallographic and Molecular Modelling Study.

The mycolic acid biosynthetic pathway represents a promising source of pharmacological targets in the fight against tuberculosis. In Mycobacterium tuberculosis, mycolic acids are subject to specific chemical modifications introduced by a set of eight S-adenosylmethionine dependent methyltransferases. Among these, Hma (MmaA4) is responsible for the introduction of oxygenated modifications. Crystallographic screening of a library of fragments allowed the identification of seven ligands of Hma. Two mutually exclusive binding modes were identified, depending on the conformation of residues 147–154. These residues are disordered in apo-Hma but fold upon binding of the S-adenosylmethionine (SAM) cofactor as well as of analogues, resulting in the formation of the short η1-helix. One of the observed conformations would be incompatible with the presence of the cofactor, suggesting that allosteric inhibitors could be designed against Hma. Chimeric compounds were designed by fusing some of the bound fragments, and the relative binding affinities of initial fragments and evolved compounds were investigated using molecular dynamics simulation and generalised Born and Poisson–Boltzmann calculations coupled to the surface area continuum solvation method. Molecular dynamics simulations were also performed on apo-Hma to assess the structural plasticity of the unliganded protein. Our results indicate a significant improvement in the binding properties of the designed compounds, suggesting that they could be further optimised to inhibit Hma activity.

Explanation of the Formation of Complexes between Representatives of Oxazolidinones and HDAS-β-CD Using Molecular Modeling as a Complementary Technique to cEKC and NMR.

Molecular modeling (MM) results for tedizolid and radezolid with heptakis-(2,3-diacetyl-6-sulfo)-β-cyclodextrin (HDAS-β-CD) are presented and compared with the results previously obtained for linezolid and sutezolid. The mechanism of interaction of chiral oxazolidinone ligands belonging to a new class of antibacterial agents, such as linezolid, tedizolid, radezolid, and sutezolid, with HDAS-β-CD based on capillary electrokinetic chromatography (cEKC), nuclear magnetic resonance (NMR) spectroscopy, and MM methods was described. Principles of chiral separation of oxazolidinone analogues using charged single isomer derivatives of cyclodextrin by the cEKC method were presented, including the selection of the optimal chiral selector and separation conditions, complex stoichiometry, and binding constants, which provided a comprehensive basis for MM studies. In turn, NMR provided, where possible, direct information on the geometry of the inclusion complexes and also provided the necessary structural information to validate the MM calculations. Consequently, MM contributed to the understanding of the structure of diastereomeric complexes, the thermodynamics of complexation, and the visualization of their structures. The most probable mean geometries of the studied supramolecular complexes and their dynamics (geometry changes over time) were determined by molecular dynamics methods. Oxazolidinone ligands have been shown to complex mainly the inner part of cyclodextrin, while the external binding is less privileged, which is consistent with the conclusions of the NMR studies. Enthalpy values of binding of complexes were calculated using long-term molecular dynamics in explicit water as well as using molecular mechanics, the Poisson–Boltzmann or generalized Born, and surface area continuum solvation (MM/PBSA and MM/GBSA) methods. Computational methods predicted the effect of changes in pH and composition of the solution on the strength and complexation process, and it adapted the conditions selected as optimal during the cEKC study. By changing the dielectric constant in the MM/PBSA and MM/GBSA calculations, the effect of changing the solution to methanol/acetonitrile was investigated. A fairly successful attempt was made to predict the chiral separation of the oxazolidinones using the modified cyclodextrin by computational methods.

Druggability assessment of precursor membrane protein as a target for inhibiting the Zika virus

The Zika virus (ZIKV), a significant zoonotic flavivirus, was neglected as a human pathogen until the recent epidemic. The rapid geographic spread of the virus and association with neurological disorders has created a global public health concern pressing the need for anti-ZIKV drugs. Previous ZIKV drug discovery research has focused on three primary targets, RNA-dependent RNA polymerase, envelope protein, and viral proteases, and none has yet resulted in a commercially viable inhibitor. In the quest for finding effective inhibitors, it is important to expand the number of targets available for drug discovery research. To this end, the ZIKV precursor membrane protein (prM) comes to the forefront as a potential target due to its critical role in virus infectivity and pathogenicity. prM acts as a chaperone for envelope protein folding and prevents premature fusion of virions to the host membrane and has not been attempted as a drug target before. One critical requirement for a protein to be an effective target is the ability of the protein to be druggable, i.e. having active sites that can bind to specific ligands. In this work, the druggability of prM was assessed via molecular docking combined molecular dynamics simulations followed binding affinity kinetics studies. Compounds that had a high affinity to the prM protein were screened in silico and ligand-binding free energies were computed using molecular mechanics with generalized Born and surface area continuum solvation (MM-GBSA) method. In vitro binding kinetics via biolayer interferometry (BLI) and interaction analysis confirmed that prM could be targeted for drug discovery to combat ZIKV infection. Communicated by Ramaswamy H. Sarma

Solvation at metal/water interfaces: An ab initio molecular dynamics benchmark of common computational approaches.

Determining the influence of the solvent on electrochemical reaction energetics is a central challenge in our understanding of electrochemical interfaces. To date, it is unclear how well existing methods predict solvation energies at solid/liquid interfaces, since they cannot be assessed experimentally. Ab initio molecular dynamics (AIMD) simulations present a physically highly accurate, but also a very costly approach. In this work, we employ extensive AIMD simulations to benchmark solvation at charge-neutral metal/water interfaces against commonly applied continuum solvent models. We consider a variety of adsorbates including *CO, *CHO, *COH, *OCCHO, *OH, and *OOH on Cu, Au, and Pt facets solvated by water. The surfaces and adsorbates considered are relevant, among other reactions, to electrochemical CO2 reduction and the oxygen redox reactions. We determine directional hydrogen bonds and steric water competition to be critical for a correct description of solvation at the metal/water interfaces. As a consequence, we find that the most frequently applied continuum solvation methods, which do not yet capture these properties, do not presently provide more accurate energetics over simulations in vacuum. We find most of the computed benchmark solvation energies to linearly scale with hydrogen bonding or competitive water adsorption, which strongly differ across surfaces. Thus, we determine solvation energies of adsorbates to be non-transferable between metal surfaces, in contrast to standard practice.

Reconciling Work Functions and Adsorption Enthalpies for Implicit Solvent Models: A Pt (111)/Water Interface Case Study.

Implicit solvent models are a computationally efficient method of representing solid/liquid interfaces prevalent in electrocatalysis, energy storage, and materials science. However, electronic structure changes induced at the metallic surface by the dielectric continuum are not fully understood. To address this, we perform DFT calculations for the Pt(111)/water interface, in order to compare Poisson-Boltzmann continuum solvation methods with ab initio molecular dynamics (AIMD) simulations of explicit solvent. We show that the implicit solvent cavity can be parametrized in terms of the electric dipole moment change at the equilibrated explicit Pt/water interface to obtain the potential of zero charge (PZC). We also compare the accuracy of aqueous enthalpies of adsorption of phenol on Pt(111) using geometry and charge density based dielectric cavitation methods. The ability to parametrize the cavity according to individual atoms, as afforded in the geometry based approach, is key to obtaining accurate enthalpy changes of adsorption under aqueous conditions. We also show that the electronic structure changes induced by explicit solvent and our proposed implicit solvent parametrization scheme yield comparable density difference profiles and d-band projected density of states. We therefore demonstrate the capability of implicit solvent approaches to capture both the energetics of adsorption processes and the main electronic effects of aqueous solvent on the metallic surface. This work therefore provides a scheme for computationally efficient simulations of interfacial processes for applications in areas such as heterogeneous catalysis and electrochemistry.

Effects of surface charge and cluster size on the electrochemical dissolution of platinum nanoparticles using COMB3 and continuum electrolyte models.

We study the site-dependent dissolution of platinum nanoparticles under electrochemical conditions to assess their thermodynamic stability as a function of shape and size using empirical molecular dynamics and electronic-structure models. The third-generation charge optimized many-body potential is employed to determine the validity of uniform spherical representations of the nanoparticles in predicting dissolution potentials (the Kelvin model). To understand the early stages of catalyst dissolution, implicit solvation techniques based on the self-consistent continuum solvation method are applied. It is demonstrated that interfacial charge and polarization can shift the dissolution energies by amounts on the order of 0.74 eV depending on the surface site and nanoparticle shape, leading to the unexpected preferential removal of platinum cations from highly coordinated sites in some cases.

Field-Aware Interfaces in Continuum Solvation.

Continuum models of solvation are widespread tools for the prediction of solvation free energies of small molecular compounds from first principles. However, the continuum approximation at the core of these approaches limits their accuracy for the modeling of the aqueous solvation of compounds with highly polarized residue or of charged species. This is due to the fact that straightforward definitions of the continuum interface do not account for the reorganization effects induced by these solutes on the positions of surrounding solvent molecules. This kind of problem is usually overcome by stretching the definition of the continuum model, i.e., by using chemical intuition to adjust (usually shrinking) the size of the solvation interface close to the polarized/charged atoms. Nonetheless, this strategy introduces a significant number of additional parameters that need to be tuned and, at the same time, deters the model's transferability. A transferable solution is instead represented by an improved definition of the continuum interface, able to automatically account for the polarization/charge state of the embedded system. Following recent approaches in the literature, the component of the solute's electric field normal to the interface can be used as an effective proxy for the net charge of the embedded system. Here we show a simple definition of this field-aware approach as applied to the recently proposed soft-sphere continuum solvation (SSCS) method. In this model, each soft sphere composing the interface is allowed to readjust as a function of the value of the field flux through its surface. This effect introduces a complex dependence of the interface function on both the electronic and the ionic degrees of freedom of the solute. To account for this dependence during optimization procedures (e.g., the SCF loop and geometry optimization algorithms), the analytic derivatives of the new interface are reported and validated with their numerical counterparts. Application of the field-aware procedure to molecular compounds showing pathological behaviors with the standard SSCS approach show that significant improvements can be achieved by specifically tuning the newly introduced parameters.

Experimental and computational study of the pKa of coumaric acid derivatives

The dissociation constant (pKa) of a drug is a key parameter in drug discovery and pharmaceutical formulation. The hydroxy substituent has a significant effect on the acidity of hydroxycinnamic acid. In this work, the acidic constants of coumaric acids are obtained experimentally by spectrophotometry using the chemometric method and calculated theoretically using ab initio quantum mechanical method at the HF/6‐31G* level of theory in combination with the SMD continuum solvation method. Rank annihilation factor analysis (RAFA) is an efficient chemometric technique based on the elimination of the contribution of one of the chemical components from the data matrix. RAFA cannot be performed because the pure spectrum of HA− is not available. So, two‐rank annihilation factor analysis (TRAFA) is proposed for the determination of the pKa OF H2A. A comparison between the pKa values obtained previously by TRAFA for the molecules o‐coumaric acid (4.13, 9.58), m‐coumaric acid (4.48, 10.35), and p‐coumaric acid (4.65, 9.92) makes it clear that there is good agreement between the results obtained by TRAFA and ab initio quantum mechanical method.

Affinity Calculations of Cyclodextrin Host-Guest Complexes: Assessment of Strengths and Weaknesses of End-Point Free Energy Methods.

The end-point methods like MM/PBSA or MM/GBSA estimate the free energy of a biomolecule by combining its molecular mechanics energy with solvation free energy and entropy terms. On the one hand, their performance largely depends on the particular system of interest, and despite numerous attempts to improve their reliability that have resulted in many variants, there is still no clear alternative to improve their accuracy. On the other hand, the relatively small cyclodextrin host-guest complexes, for which high-quality binding calorimetric data are usually available, are becoming reference models for testing the accuracy of free energy methods. In this work, we further assess the performance of various MM/PBSA-like approaches as applied to cyclodextrin complexes. To this end, we select a set of complexes between β-cyclodextrin and 57 small organic molecules that has been previously studied with the binding energy distribution analysis method in combination with an implicit solvent model ( Wickstrom, L.; He, P.; Gallicchio, E.; Levy, R. M. J. Chem. Theory Comput. 2013 , 9 , 3136 - 3150 ). For each complex, a conventional 1.0 μs molecular dynamics simulation in explicit solvent is performed. Then we employ semiempirical quantum chemical calculations, several variants of the MM-PB(GB)SA methods, entropy estimations, etc., to assess the reliability of the end-point affinity calculations. The best end-point protocol in this study, which combines DFTB3 energies with entropy corrections, yields estimations of the binding free energies that still have substantial errors (RMSE = 2.2 kcal/mol), but it exhibits a good prediction capacity in terms of ligand ranking ( R2 = 0.66) that is close to or even better than that of rigorous free energy methodologies. Our results can be helpful to discriminate between the intrinsic limitations of the end-point methods and other sources of error, such as the underlying energy and continuum solvation methods.

Synthesis, spectroscopic characterization and DFT/TD-DFT computations of a novel charge transfer complex via hydrogen bonding between 3-amino-1,5-dimethylpyrazole with chloranilic acid in different solvents

A novel charge transfer complex including hydrogen bonding between the e-donor (H-acceptor) 3-amino-1,5-dimethylpyrazole (3-ADMP) with the e-acceptor (H-donor) chloranilic acid (CLA) has been synthesized and characterized experimentally and theoretically. The experimental work was carried out in different solvents including chloroform (CHL), ethanol (EtOH), methanol (MeOH) and acetonitrile (AN). The solution characterizations included the determining of the molecular composition of the formed CT complex where it recorded 1:1 (donor:acceptor) in all solvent. Also, estimating its formation constant by Benesie-Hildebrand equation where it recorded high values in all solvents, suggesting its high stability. Thermodynamic and some spectroscopic physical parameters were introduced and interpreted where they confirmed the presence of charge transfer besides hydrogen bonding in the formed complex. The solid complex was prepared and characterized by elemental analysis, infrared and NMR (1H and 13C) spectroscopies, the complex was formed in 1:1 ratio, with good evidences for existing both charge transfer and hydrogen bonding in its molecular structure. Density functional theory B3LYP-DFT at the basis set 6-31G (d,p) has been running out in gas phase and solution using chloroform and acetonitrile as solvents to compliment the measured results. The complex optimized structure included two hydrogen bonds between OH and CO of chloranilic acid with the adjacent ring nitrogen and amino group of pyrazole ring. The optimization energy, complexation energy, geometrical parameters, Mullikan atomic charges as well as molecular electrostatic potential maps (MEP) were calculated and interpreted; they consisted with the experimental results where the complex stability is attributed to the presence of H-bond beside e-transfer. The electronic spectra were computed using TD-DFT through adding polarizable continuum solvation method PCM, PCM-TD-DFT to compare with the experimental results. It has been found that, the measured and computed λmax are coming close to each other. The allowed singlet transitions are located and their HOMO and LUMO contributions are presented. The pictures of the frontier HOMO and LUMO molecular orbitals, participating in the first six singlet transitions were presented. A good consistency between experimental and DFT computations has been found.