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The speciation and characteristics of silica in water at standard conditions are still poorly understood. Using density functional theory, the plausible existence of the zwitterion isomer of orthosilicic acid is proposed to account for some of the properties of silica in neutral pH water. Explicit hydration and explicit addition of salt are used in modeling the zwitterion and the dimerization reaction. Paths between orthosilicic acid, the zwitterion and the acid dissociation products are presented. Implicit solvation free energies and quasi-harmonic corrections are evaluated. The pK for the formation of the aqueous zwitterion species is calculated to be 6.5 in dilute silica solutions and the activation energy for the dimerization reaction ranges from 59.7 kJ/mol to 70.7 kJ/mol depending on salt concentration in agreement with experiment. [ABSTRACT FROM AUTHOR]

Predicting solvation free energies and describing the complex water behavior that plays an important role in essentially all biological processes is a major challenge from the computational standpoint. While an atomistic, explicit description of the solvent can turn out to be too expensive in large biomolecular systems, most implicit solvent methods fail to capture "dewetting" effects and heterogeneous hydration by relying on a pre-established (i.e., guessed) solvation interface. Here we focus on the Variational Implicit Solvent Method, an implicit solvent method that adds water "plasticity" back to the picture by formulating the solvation free energy as a functional of all possible solvation interfaces. We survey VISM's applications to the problem of molecular recognition and report some of the most recent efforts to tailor VISM for more challenging scenarios, with the ultimate goal of including thermal fluctuations into the framework. The advances reported herein pave the way to make VISM a uniquely successful approach to characterize complex solvation properties in the recognition and binding of large-scale biomolecular complexes.

In this work, we introduce an electrostatic and non‐electrostatic (ENE) correction to the solvation energy based on the Solvent‐Accessible Surface Area (SASA) of the solute and the solvent static dielectric constant. The proposed correction was developed for neutral solutes in non‐aqueous solvents, considering three different implicit solvation models based on a Self‐Consistent Reaction Field treatment of solute‐solvent mutual polarization using an Apparent Surface Charge formalism, namely the Integral Equation Formalism of the Polarizable Continuum Model using a continuous surface charge scheme (PCM), the Solvation Model based on solute electron density (SMD), and the generalized Finite‐Difference Poisson‐Boltzmann (FDPB) model. The proposed correction was parametrized on a diverse training set of 4980 solvation data from the Solv@tum database of experimental solvation energies, and validated on the non‐aqueous subset of the MNSOL database comprising 2140 solvation energies. The performances of the proposed ENE models with minimal and extended parameters formulations have been analyzed and the latter variant has been further compared to the widely used Cavity, Dispersion, and Solvent structural effects (CDS) non‐electrostatic model originally developed for the SMx family of implicit solvation models. Overall, a very good agreement between the computed solvation energies with the ENE correction and the reference experimental data has been found on both the training and test sets for all continuum solvation models considered. Furthermore, results for the ENE correction are on par with the reference CDS non‐electrostatic model for both SMD and FDPB electrostatics, but with the advantage of using a lower number of parameters and thus an improved transferability between different electrostatics treatments. [ABSTRACT FROM AUTHOR]

Rate theory and DFT calculations of hydrogen evolution reaction (HER) on MoS 2 with Co, Ni and Pt impurities show the significance of dihydrogen (H 2 *) complex where both hydrogen atoms are interacting with the surface. Stabilization of such a complex affects the competing Volmer-Heyrovsky (direct H 2 release) and Volmer-Tafel (H 2 * intermediate) pathways. The resulting evolution proceeds with a very small overpotential for all dopants ( η ${\eta }$ =0.1 to 0.2 V) at 25 % edge substitution, significantly reduced from the already low η ${\eta }$ =0.27 V for the undoped edge. At full edge substitution, Co-MoS 2 remains highly active ( η ${\eta }$ =0.18 V) while Ni- and Pt-MoS 2 are deactivated ( η ${\eta }$ =0.4 to 0.5 V) due to unfavorable interaction with H 2 *. Instead of the single S-vacancy, the site of intrinsic activity in the basal plane was found to be the undercoordinated central Mo-atom in threefold S-vacancy configurations, enabling hydrogen evolution with η ${\eta }$ =0.52 V via a H 2 * intermediate. The impurity atoms interact favorably with the intrinsic sulfur vacancies on the basal plane, stabilizing but simultaneously deactivating the triple vacancy configuration. The calculated shifts in overpotential are consistent with reported measurements, and the dependence on doping level may explain variations in experimental observations., (© 2024 Wiley-VCH GmbH.)

In protein simulation or structure refinement based on values of observable quantities measured in (aqueous) solution, solvent (water) molecules may be explicitly treated, omitted, or represented by a potential of mean-solvation-force term, depending on protein coordinates only, in the force field used. These three approaches are compared for hen egg white lysozyme (HEWL). This 129-residue non-spherical protein contains a variety of secondary-structure elements, and ample experimental data are available: 1630 atom–atom Nuclear Overhauser Enhancement (NOE) upper distance bounds, 213 3 J-couplings and 200 S2 order parameters. These data are used to compare the performance of the three approaches. It is found that a molecular dynamics (MD) simulation in explicit water approximates the experimental data much better than stochastic dynamics (SD) simulation in vacuo without or with a solvent-accessible-surface-area (SASA) implicit-solvation term added to the force field. This is due to the missing energetic and entropic contributions and hydrogen-bonding capacities of the water molecules and the missing dielectric screening effect of this high-permittivity solvent. Omission of explicit water molecules leads to compaction of the protein, an increased internal strain, distortion of exposed loop and turn regions and excessive intra-protein hydrogen bonding. As a consequence, the conformation and dynamics of groups on the surface of the protein, which may play a key role in protein–protein interactions or ligand or substrate binding, may be incorrectly modelled. It is thus recommended to include water molecules explicitly in structure refinement of proteins in aqueous solution based on nuclear magnetic resonance (NMR) or other experimentally measured data. [ABSTRACT FROM AUTHOR]

Rings are one of the major scaffold components of drugs in medicinal chemistry, due to their unique electronic distribution, scaffold rigidity, and three‐dimensionality while lipophilicity is considered as a vital parameter of rings that can influence the reactivity, metabolic stability, and toxicity. We have analyzed the electronic features, hydration patterns, solvation effect and lipophilicity data for 51 most widely used ring systems in drugs. Molecular electrostatic potential (MESP) topology analysis has been used to assess the electronic distribution in rings which provided an easy interpretation of the most suitable hydration patterns of the ring with H2O molecule. Further, the global minimum of ring...H2O complex has been utilized to predict lipophilicity (logP) with the incorporation of implicit solvation effect. Classification of ring systems based on their molecular weight into four categories, viz. small ring 'sr', medium ring 'mr', large ring 'lr' and extra large ring 'xlr' systems has led to the finding of strong correlations between logP and hydration energy with R = 0.942, 0.933, 0.968 and 0.933, respectively. The micro solvation model is found to be useful for locating the hydrophobic‐hydrophilic border for each category of rings in terms of hydration energy whereas the implicit solvation model used for two solvents, n‐octanol and water on the most stable hydrated structure led to a global correlation between logP and solvation energy ratio. This correlation predicts a limiting logP value −7.03 for the most hydrophilic ring system and also suggests a clear partitioning of the ring molecules into hydrophobic and hydrophilic classes. The MESP topology‐guided approach to understand the electronic features and hydration patterns of rings in drugs lead to powerful predictions on their lipophilicity behavior. [ABSTRACT FROM AUTHOR]

We show that a Single-Atom Electrocatalyst (SAC) for the Nitrogen Reduction Reaction (NRR) can provide an environmentally green alternative to the Haber–Bosch high-temperature high-pressure process, replacing the water gas shift production of H2 with H extracted from water. Anchoring the single atom on a two-dimensional substrate provides control to tune NRR catalytic performance toward a SAC possessing high utilization, high activity, and high selectivity. Experimental results suggest that this can significantly improve the activity and selectivity of NRR, but the specific reaction mechanism remains uncertain. This makes it difficult to select new catalytic materials for further optimization. Here we use Density Functional Theory to study the NRR catalytic mechanism on a catalytic model using a MoS2 substrate to support a single atom site. We correct for solvation effects on the electrochemical reactions. We started with Fe@MoS2, for which there are promising experimental reports, and conducted a systematic study of the NRR reaction mechanisms. These results show that N2 adsorption, hydrogenation of N2, desorption of NH3, and Hydrogen Evolution are all critical steps affecting the reaction rates. Based on these steps, we scanned 23 transition metal elements to find improved catalysts. We identified Ir@MoS2 (Mo top site) as the best candidate, predicted to have good catalytic activity and selectivity with 64.11% Faraday Efficiency. These results on the mechanism for NRR and the in silico search for alternative catalysts provide new promising targets for synthesizing novel and efficient SAC@MoS2 NRR catalysts. [ABSTRACT FROM AUTHOR]

We show that a Single-Atom Electrocatalyst (SAC) for the Nitrogen Reduction Reaction (NRR) can provide an environmentally green alternative to the Haber–Bosch high-temperature high-pressure process, replacing the water gas shift production of H2 with H extracted from water. Anchoring the single atom on a two-dimensional substrate provides control to tune NRR catalytic performance toward a SAC possessing high utilization, high activity, and high selectivity. Experimental results suggest that this can significantly improve the activity and selectivity of NRR, but the specific reaction mechanism remains uncertain. This makes it difficult to select new catalytic materials for further optimization. Here we use Density Functional Theory to study the NRR catalytic mechanism on a catalytic model using a MoS2 substrate to support a single atom site. We correct for solvation effects on the electrochemical reactions. We started with Fe@MoS2, for which there are promising experimental reports, and conducted a systematic study of the NRR reaction mechanisms. These results show that N2 adsorption, hydrogenation of N2, desorption of NH3, and Hydrogen Evolution are all critical steps affecting the reaction rates. Based on these steps, we scanned 23 transition metal elements to find improved catalysts. We identified Ir@MoS2 (Mo top site) as the best candidate, predicted to have good catalytic activity and selectivity with 64.11% Faraday Efficiency. These results on the mechanism for NRR and the in silico search for alternative catalysts provide new promising targets for synthesizing novel and efficient SAC@MoS2 NRR catalysts. [ABSTRACT FROM AUTHOR]

The spectroscopic data for a range of cyclopenta-[ d ][1,2,3]-triazine derivative dyes have been evaluated using various standard computational approaches. Absorption data of these dyes were obtained using the ZINDO/S semi-empirical model for vertical excitation energies of structures optimised with the AM1, PM3, and PM6 methods. These studies were conducted under vacuum and solution states using the polarisation continuum model (PCM) for implicit solvation in the linear response model. The accuracy, along with the modest computational costs of using the ZINDO/S prediction, combined with the PM3 optimisation method for absorption data was reliable. While a higher computational cost is required for the time-dependent density functional theory (TDDFT), this method offers a reliable method for calculating both the absorption and emission data for the dyes studied (using vertical and adiabatic excitation energies, respectively) via state-specific solvation. This research demonstrates the potential of computational approaches utilising solvation in evaluating the spectroscopic properties of dyes in the rational design of fluorescent probes. The spectroscopic analysis of cyclopenta-[ d ][1,2,3]-triazine derivatives was studied. TDDFT calculations corresponded to the experimental absorbance and emission data. Semi-empirical methods recorded a lower computational cost. [ABSTRACT FROM AUTHOR]

A nearly linear scaling implementation of coupled‐cluster with singles and doubles excitations (CCSD) can be achieved by means of the domain‐based local pair natural orbital (DLPNO) method. The combination of DLPNO‐CCSD with implicit solvation methods allows the calculation of accurate energies and chemical properties of solvated systems at an affordable computational cost. We have efficiently implemented different schemes within the conductor‐like polarizable continuum model (C‐PCM) for DLPNO‐CCSD in the ORCA quantum chemistry suite. In our implementation, the overhead due to the additional solvent terms amounts to less than 5% of the time the equivalent gas phase job takes. Our results for organic neutrals and open‐shell ions in water show that for most systems, adding solvation terms to the coupled‐cluster amplitudes equations and to the energy leads to small changes in the total energy compared to only considering solvated orbitals and corrections to the reference energy. However, when the solute contains certain functional groups, such as carbonyl or nitrile groups, the changes in the energy are larger and estimated to be around 0.04 and 0.02 kcal/mol for each carbonyl and nitrile group in the solute, respectively. For solutes containing metals, the use of accurate CC/C‐PCM schemes is crucial to account for correlation solvation effects. Simultaneously, we have calculated the electrostatic component of the solvation energy for neutrals and ions in water for the different DLPNO‐CCSD/C‐PCM schemes. We observe negligible changes in the deviation between DLPNO‐CCSD and canonical‐CCSD data. Here, DLPNO‐CCSD results outperform those for Hartree‐Fock and density functional theory calculations. [ABSTRACT FROM AUTHOR]

This review describes the theory and implementation of implicit solvation models based on continuum electrostatics. Within quantum chemistry this formalism is sometimes synonymous with the polarizable continuum model, a particular boundary‐element approach to the problem defined by the Poisson or Poisson–Boltzmann equation, but that moniker belies the diversity of available methods. This work reviews the current state‐of‐the art, with emphasis on theory and methods rather than applications. The basics of continuum electrostatics are described, including the nonequilibrium polarization response upon excitation or ionization of the solute. Nonelectrostatic interactions, which must be included in the model in order to obtain accurate solvation energies, are also described. Numerical techniques for implementing the equations are discussed, including linear‐scaling algorithms that can be used in classical or mixed quantum/classical biomolecular electrostatics calculations. Anisotropic models that can describe interfacial solvation are briefly described. This article is categorized under:Electronic Structure Theory > Ab Initio Electronic Structure MethodsMolecular and Statistical Mechanics > Free Energy Methods [ABSTRACT FROM AUTHOR]

In this work, we investigate the effects of different atomic charge and nonelectrostatic models on the hydration energies of neutral molecules, using an implicit solvation model. The solvation free energy is divided into two main components, the first resulting from a self‐consistent reaction field treatment of the bulk electrostatics obtained by solving the Poisson equation in a finite‐difference (FD) approach where the solute charge density is approximated by atomic charges, the second corresponding to short‐range interactions between the solute and the solvent in the first solvation shell. Five different atomic charge models (Mulliken, Hirshfeld, Hirshfeld‐I, CM5 and its iterative version, CM5‐I) have been considered, both at the Hartree–Fock (HF) and B3LYP levels, with three different basis sets, alongside two nonelectrostatic models including the cavity, dispersion, and solvent structural effects (CDS) model. Averaging over the three considered basis sets, Hirshfeld charges combined to the CDS model led to the lowest mean unsigned error (MUE), with a value of 0.92 kcal/mol with respect to the experimental data. On the other hand, a MUE of 2.02 kcal/mol was obtained with CM5 charges combined to the CDS model, highlighting the low transferability of the original CDS parameters developed for the generalized Born electrostatics to a different electrostatics model. By scaling down the CM5 charges to better balance with the original CDS model, a MUE of 0.68 kcal/mol was however obtained, outlining the delicate balance existing between the electrostatic and nonelectrostatic contributions to the solvation free energy in implicit solvation models. [ABSTRACT FROM AUTHOR]

The semiempirical INDO/S Hamiltonian is incorporated into a new release of MOPAC2016. The MOPAC2016 software package has long been at the forefront of semiempirical quantum chemical methods (SEQMs) for small molecules, proteins, and solids and until this release has included only NDDO‐type SEQMs. The new code enables the calculation of excited states using the INDO/S Hamiltonian combined with a configuration interaction (CI) approach using single excitations (CIS), single and double excitations (CISD), or multiple reference determinants (MRCI) where reference determinants are generated using a complete active space (CAS) approach. The capacity to perform excited‐state calculations beyond the CIS level makes INDO/CI one of the few low‐cost computational methods capable of accurately modeling states with substantial double‐excitation character. Solvent corrections to the ground‐state and excited‐state energies can be computed using the COSMO implicit solvent model, incorporating state‐specific corrections to the excited states based on the solvent refractive index. This code produces physically reasonable electronic structures, absorption spectra, and solvatochromic shifts at low computational costs for systems up to hundreds of atoms, and for both organic molecules and metal clusters. [ABSTRACT FROM AUTHOR]

In this article, we explore an alternative to the analytical Gauss–Bonnet approach for computing the solvent‐accessible surface area (SASA) and its nuclear gradients. These two key quantities are required to evaluate the nonelectrostatic contribution to the solvation energy and its nuclear gradients in implicit solvation models. We extend a previously proposed analytical approach for finite systems based on the stereographic projection technique to infinite periodic systems such as polymers, nanotubes, helices, or surfaces and detail its implementation in the Crystal code. We provide the full derivation of the SASA nuclear gradients, and introduce an iterative perturbation scheme of the atomic coordinates to stabilize the gradients calculation for certain difficult symmetric systems. An excellent agreement of computed SASA with reference analytical values is found for finite systems, while the SASA size‐extensivity is verified for infinite periodic systems. In addition, correctness of the analytical gradients is confirmed by the excellent agreement obtained with numerical gradients and by the translational invariance achieved, both for finite and infinite periodic systems. Overall therefore, the stereographic projection approach appears as a general, simple, and efficient technique to compute the key quantities required for the calculation of the nonelectrostatic contribution to the solvation energy and its nuclear gradients in implicit solvation models applicable to both finite and infinite periodic systems. [ABSTRACT FROM AUTHOR]

Theoretical approaches for predicting physicochemical properties are valuable tools for accelerating the drug discovery process. In this work, quantum chemical methods are used to predict water–octanol partition coefficients as a part of the SAMPL6 blind challenge. The SMD continuum solvent model was employed with MP2 and eight DFT functionals in conjunction with correlation consistent basis sets to determine the water–octanol transfer free energy. Several tactics towards improving the predictions of the partition coefficient were examined, including increasing the quality of basis sets, considering tautomerization, and accounting for inhomogeneities in the water and n-octanol phases. Evaluation of these various schemes highlights the impact of modeling approaches across different methods. With the inclusion of tautomers and adjustments to the permittivity constants, the best predictions were obtained with smaller basis sets and the O3LYP functional, which yielded an RMSE of 0.79 logP units. The results presented correspond to the SAMPL6 logP submission IDs: DYXBT, O7DJK, and AHMTF. [ABSTRACT FROM AUTHOR]

This work presents a quantum mechanical model for predicting octanol-water partition coefficients of small protein-kinase inhibitor fragments as part of the SAMPL6 LogP Prediction Challenge. The model calculates solvation free energy differences using the M06-2X functional with SMD implicit solvation and the def2-SVP basis set. This model was identified as dqxk4 in the SAMPL6 Challenge and was the third highest performing model in the physical methods category with 0.49 log Root Mean Squared Error (RMSE) for predicting the 11 compounds in SAMPL6 blind prediction set. We also collaboratively investigated the use of empirical models to address model deficiencies for halogenated compounds at minimal additional computational cost. A mixed model consisting of the dqxk4 physical and hdpuj empirical models found improved performance at 0.34 log RMSE on the SAMPL6 dataset. This collaborative mixed model approach shows how empirical models can be leveraged to expediently improve performance in chemical spaces that are difficult for ab initio methods to simulate. [ABSTRACT FROM AUTHOR]

The treatment of the solvation charges using Gaussian functions in the polarizable continuum model results in a smooth potential energy surface. These charges are placed on top of the surface of the solute cavity. In this article, we study the effect of the solute cavity (van der Waals‐type or solvent‐excluded surface‐type) using the Gaussian charge scheme within the framework of the conductor‐like polarizable continuum model on (a) the accuracy and computational cost of the self‐consistent field (SCF) energy and its gradient and on (b) the calculation of free energies of solvation. For that purpose, we have considered a large set of systems ranging from few atoms to more than 200 atoms in different solvents. Our results at the DFT level using the B3LYP functional and the def2‐TZVP basis set show that the choice of the solute cavity does neither affect the accuracy nor the cost of calculations for small systems (< 100 atoms). For larger systems, the use of a vdW‐type cavity is recommended, as it prevents small oscillations in the gradient (present when using a SES‐type cavity), which affect the convergence of the SCF energy gradient. Regarding the free energies of solvation, we consider a solvent‐dependent probe sphere to construct the solvent‐accessible surface area required to calculate the nonelectrostatic contribution to the free energy of solvation. For this part, our results for a large set of organic molecules in different solvents agree with available experimental data with an accuracy lower than 1 kcal/mol for both polar and nonpolar solvents. [ABSTRACT FROM AUTHOR]

Three implicit solvation models, the conductor‐like polarizable continuum model (C‐PCM), the conductor‐like screening model (COSMO), and universal implicit solvent model (SMD), combined with a hybrid two layer QM/QM approach (ONIOM), were utilized to calculate the pKa values, using a direct thermodynamic scheme, of a set of Group 10 transition metal (TM) hydrides in acetonitrile. To obtain the optimal combination of quantum methods for ONIOM calculations with implicit solvation models, the influence of factors, such as the choice of density functional and basis set, the atomic radii used to build a cavity in the solvent, and the size of the model system in an ONIOM scheme, was examined. Additionally, the impact of Grimme's empirical dispersion correction and exact exchange was also investigated. The results were calibrated by experimental data. This investigation provides insight about effective models for the prediction of thermodynamic properties of TM‐containing complexes with bulky ligands. © 2019 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Upon activation, fibrinogen is converted to insoluble fibrin, which assembles into long strings called protofibrils. These aggregate laterally to form a fibrin matrix that stabilizes a blood clot. Lateral aggregation of protofibrils is mediated by the αC domain, a partially structured fragment located in a disordered region of fibrinogen. Polymerization of αC domains links multiple fibrin molecules with each other enabling the formation of thick fibrin fibers and a fibrin matrix that is stable but can also be digested by enzymes. However, oxidizing agents produced during the inflammatory response have been shown to cause thinner fibrin fibers resulting in denser clots, which are harder to proteolyze and pose the risk of deep vein thrombosis and lung embolism. Oxidation of Met476 located within the αC domain is thought to hinder its ability to polymerize disrupting the lateral aggregation of protofibrils and leading to the observed thinner fibers. How αC domains assemble into polymers is still unclear and yet this knowledge would shed light on the mechanism through which oxidation weakens the lateral aggregation of protofibrils. This study used temperature replica exchange molecular dynamics simulations to investigate the αC‐domain dimer and how this is affected by oxidation of Met476. Analysis of the trajectories revealed that multiple stable binding modes were sampled between two αC domains while oxidation decreased the likelihood of dimer formation. Furthermore, the side chain of Met476 was observed to act as a docking spot for the binding and this function was impaired by its conversion to methionine sulfoxide. [ABSTRACT FROM AUTHOR]

Calculation of vibrational frequencies for solvated systems is essential to study reactions in complex environments. In this paper, we report the implementation of the analytical self‐consistent field Hessian at the Hartree–Fock and density functional theory levels in the framework of the conductor‐like polarizable continuum model (C‐PCM) into the ORCA quantum chemistry suite. The calculated vibrational frequencies agree very well with those computed through numerical differentiation of the analytical gradients. The deviation between both sets of data is smaller than 3 cm−1 for frequencies larger than 200 cm−1 and smaller than 5 cm−1 for the low‐frequency regime (100 cm−1 < ω < 200 cm−1). The accuracy of the frequencies is not significantly affected by the size of the density functional theory (DFT) integration grid, with a deviation lower than 0.5 cm−1 between data computed with the smallest and that with the largest DFT grid size. The calculation of the analytical Hessian is between 3 and 12 times faster than its numerical counterpart. The C‐PCM terms only add an overhead of 10–30% relative to the gas phase calculations. Finally, for acetone, the (B3LYP) values for the frequency shifts obtained in going from the gas phase to liquid acetone are in agreement with experiment. © 2019 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

It would often be useful in computer simulations to use an implicit description of solvation effects, instead of explicitly representing the individual solvent molecules. Continuum dielectric models often work well in describing the thermodynamic aspects of aqueous solvation and can be very efficient compared to the explicit treatment of the solvent. Here, we review a particular class of so-called fast implicit solvent models, generalized Born (GB) models, which are widely used for molecular dynamics (MD) simulations of proteins and nucleic acids. These approaches model hydration effects and provide solvent-dependent forces with efficiencies comparable to molecular-mechanics calculations on the solute alone; as such, they can be incorporated into MD or other conformational searching strategies in a straightforward manner. The foundations of the GB model are reviewed, followed by examples of newer, emerging models and examples of important applications. We discuss their strengths and weaknesses, both for fidelity to the underlying continuum model and for the ability to replace explicit consideration of solvent molecules in macromolecular simulations. [ABSTRACT FROM AUTHOR]

Predicting solvation free energies and describing the complex water behavior that plays an important role in essentially all biological processes is a major challenge from the computational standpoint. While an atomistic, explicit description of the solvent can turn out to be too expensive in large biomolecular systems, most implicit solvent methods fail to capture “dewetting” effects and heterogeneous hydration by relying on a pre-established (i.e., guessed) solvation interface. Here we focus on the Variational Implicit Solvent Method, an implicit solvent method that adds water “plasticity” back to the picture by formulating the solvation free energy as a functional of all possible solvation interfaces. We survey VISM's applications to the problem of molecular recognition and report some of the most recent efforts to tailor VISM for more challenging scenarios, with the ultimate goal of including thermal fluctuations into the framework. The advances reported herein pave the way to make VISM a uniquely successful approach to characterize complex solvation properties in the recognition and binding of large-scale biomolecular complexes.

Explicit solvent molecular dynamics simulations of a macromolecule are slow as the number of solvent atoms considered typically increases by order of magnitude. Implicit methods introduce surface-dependent corrections to the force field, gaining speed at the expense of accuracy. Properties such as molecular interface surfaces, volumes and cavities are captured by Laguerre tessellations of macromolecules. However, Laguerre cells of exterior atoms tend to be overly large or unbounded. Our method, the inclusion-exclusion based Laguerre-Intersection method, caps cells in a physically accurate manner by considering the intersection of the space-filling diagram with the Laguerre tessellation. We optimize an adjustable parameter, the weight, to ensure the areas and volumes of capped cells exposed to solvent are as close as possible, on average, to those computed from equilibrated explicit solvent simulations. The contact planes are radical planes, meaning that as the solvent weight is varied, interior cells remain constant. We test the consistency of our model using a high-quality trajectory of HIV-protease, a dimer with flexible loops and open-close transitions. We also compare our results with interval-arithmetic Gauss-Bonnet based method. Optimal solvent parameters quickly converge, which we use to illustrate the increased fidelity of the Laguerre-Intersection method over two recently proposed methods as compared to the explicit model. [ABSTRACT FROM AUTHOR]

With an endeavour to improve the bioavailability profile of Tyrosine kinase inhibitors (TKI's) viz. gefitinib, regorafenib and sunitinib, the drug carrier based on calix[ n ]arene macrocycles has been proposed. A total of 72 calix[ n ]arene-TKI's complexes with the functionalized upper rim (SO 3 H, tert-Butyl, isoPropyl, COOH, C 2 H 5 OH, and C 2 H 5 NH 2 ) calix[ n ]arene ( n = 4,5,6,8) were theoretically studied to form most probable inclusion complex. Subsequently, the intermolecular interactions were explored via complementary-shape based method and Molecular Mechanics-Generalised Born Molecular Volume (MM-GBMV) calculations. We reported that the promising calix[ n ]arenes for gefitinib ( i-Pr /C 2 H 5 NH 2 -calix[5]arene, t-Bu / i-Pr -calix[6]arene and C 2 H 5 NH 2 /C 2 H 5 OH-calix[8]arene), sunitnib (SO 3 H/ t-Bu /C 2 H 5 OH-calix[8]arene, t-Bu -calix[6]arene) and for regorafenib (C 2 H 5 OH-calix[5]arene, t-Bu / i-Pr -calix[6]arene and COOH-calix[8]arene) have the greater capability to act as drug carrier. [ABSTRACT FROM AUTHOR]