Free Energy Of Association Research Articles

Effect of functionalization on the adsorption performance of carbon nanotube as a drug delivery system for imatinib: molecular simulation study

In this study, efficiency of functionalized carbon nanotube as a potential delivery system for imatinib anti-cancer drug was investigated. Accordingly, carboxyl and hydroxyl functionalized carbon nanotube were inspected as a notable candidate for the carriage of this drug in aqueous media. For this purpose, possible interactions of imatinib with pure and functionalized carbon nanotube were considered in aqueous media. The compounds were optimized in gas phase using density functional calculations. Solvation free energies and association free energies of the optimized structures were then studied by Monte Carlo simulation and perturbation method in water environment. Outcomes of quantum mechanical calculations presented that pure and functionalized carbon nanotubes can act as imatinib drug adsorbents in gas phase. However, results of association free energy calculations in aqueous solution indicated that only carboxyl and hydroxyl functionalized carbon nanotubes could interact with imatinib. Monte Carlo simulation results revealed that electrostatic interactions play a vital role in the intermolecular interaction energies after binding of drug and nanotube in aqueous solution. Computed solvation free energies in water showed that the interactions with functionalized carbon nanotubes significantly enhance the solubility of imatinib, which could improve its in vivo bioavailability.

Interaction of sulfasalazine with outer surface of boron-nitride nanotube as a drug carrier in aqueous solution: insights from quantum mechanics and Monte Carlo simulation

The improvement of the solubility of sulfasalazine in physiological media was the major aim of this study. Accordingly, BNNT inspected as a notable candidate for the carriage of this drug in aqueous media. For this purpose, four possible interactions of two tautomer of sulfasalazine with (9,0) boron-nitride nanotube were considered in aqueous media. The compounds were optimized in gas phase using density functional calculations. Solvation free energies and association free energies of the optimized structures were then studied by Monte Carlo simulation and perturbation method in water environment. Outcomes of quantum mechanical calculations presented that interaction of keto form of sulfasalazine produce the most stable complexes with boron-nitride nanotube in gas phase. Simulation results revealed that electrostatic interactions play a vital role in the intermolecular interaction energies after binding of drug and nanotube in aqueous solution. Results of association free energy calculations indicated that complexes of both two sulfasalazine tautomers (keto and enol) and nanotube were stable in solution. Computed solvation free energies in water showed that the interaction with boron-nitride nanotube significantly improved the solubility of sulfasalazine, which could improve its in vivo bioavailability.

Dispersion Energy-Stabilized Boron and Phosphorus Lewis Pairs.

An isostructural series of boron/phosphorus Lewis pairs was systematically investigated. The association constants of the Lewis pairs were determined at variable temperatures, enabling the extraction of thermodynamic parameters. The stabilization of the Lewis adduct increased with increasing size of the dispersion energy donor groups, although the donor and acceptor properties of the Lewis pairs remained largely unchanged. This data was utilized to challenge state-of-the-art quantum chemical methods, which finally led to an enhanced workflow for the determination of thermochemical properties of weakly bound Lewis pairs within an accuracy of 0.6 to 1.0 kcal mol-1 for computed association free energies.

Dispersion Energy‐Stabilized Boron and Phosphorus Lewis Pairs

AbstractAn isostructural series of boron/phosphorus Lewis pairs was systematically investigated. The association constants of the Lewis pairs were determined at variable temperatures, enabling the extraction of thermodynamic parameters. The stabilization of the Lewis adduct increased with increasing size of the dispersion energy donor groups, although the donor and acceptor properties of the Lewis pairs remained largely unchanged. This data was utilized to challenge state‐of‐the‐art quantum chemical methods, which finally led to an enhanced workflow for the determination of thermochemical properties of weakly bound Lewis pairs within an accuracy of 0.6 to 1.0 kcal mol−1 for computed association free energies.

Parameters for the conductometric association for lump and nano CoSO4.7H2O in the presence and absence of fuchsin acid in water at different temperature

ABSTRACT. For lump and nanocobalt sulfate (CoSO4) in pure water, the affiliation and thermodynamic association characteristics were measured at 298.15, 303.15, 308.15, and 313.15 K. Based on the bulk and nano CoSO4 molar conductance, estimates were made for the parameters of the solvation, such as the activity coefficient, free energy of association, enthalpy of association, association constant, and entropy of association. We discussed about each of these solvation parameters. Two stoichiometric complexes were formed by the interaction of bulk and nano CoSO4.7H2O with fuchsin acid: 1:1 and 1:2 In the case of 1:1 (CoSO4.7H2O/fuchsin acid) compared to 1:2 (fuchsin acid in pure water as solvent), the complex Kf and ∆Gf are higher, indicating simpler complex formation. The temperature increase resulted in a drop in the formation constants. The complexation's negative ∆Gf values demonstrate that the process of complex synthesis was spontaneous and that the temperature improved the spontaneity.
 
 KEY WORDS: Molar conductance, Association constants, Fuchsin acid, Nano cobalt sulfate salt, Formation constant
 
 Bull. Chem. Soc. Ethiop. 2023, 37(3), 789-804. 
 DOI: https://dx.doi.org/10.4314/bcse.v37i3.20

Lipid modulation of membrane protein conformational equilibria does not require lipid immobilization in long-lasting protein-lipid complexes.

Lipid regulation of membrane proteins is widely rationalized as a process whereby lipid molecules become immobilized in a complex with the protein, supposedly due to strong, specific interactions. While this conventional paradigm might apply to some regulatory processes, we posit that it is not a universal mechanism. As a counterexample, we examine the mechanism by which lipids modulate the dimerization reaction of the bacterial CL−/H+ antiporter CLC-ec1. Using molecular simulations, we have shown that monomeric CLC-ec1 induces a pronounced defect in the morphology of the surrounding membrane, including thinning of the hydrophobic core due to drastic lipid tilting and entanglement of the two bilayer leaflets. Upon dimerization, this interface becomes buried, and the morphological defect in the membrane is completely eliminated. Using advanced simulation methods, we have shown that the free-energy gain resulting from the elimination of this defect accounts for much of the free-energy of CLC-ec1 association measured experimentally. These experiments, based on single-molecule microscopy, also demonstrate that introduction of short-chain lipids drastically destabilize dimerization, but the concentration dependence of this inhibitory effect is incoherent with a conventional competitive ligand-binding process. To examine the microscopic mechanism underlying these intriguing observations, we calculate a continuous 40-microsecond molecular dynamics trajectory of all-atom monomeric CLC-ec1 embedded in a 70:30 mixture of POPC and DLPC lipids. This simulation shows that DLPC molecules become enriched within the thinned-membrane defect, alleviating its energetic cost and hence inhibits dimerization. However, we find that this enrichment does not stem from the immobilization of these lipids in a long-lasting protein-lipid complex, but from subtle yet statistically significant differences in the residence times and exchange frequency of PO and DL lipids within the first solvation shells.

Computer simulation and modeling the metal to insulating transition of liquid mercury via pair, empirical, and many-body potentials.

In this study, Monte Carlo simulations were carried out to detect the metal-insulator transition in liquid mercury by changing the static properties at the microscopic scale. In the simulations pair, empirical, and many-body potentials govern metal-metal interactions in the canonical ensemble. The structural and thermodynamic changes over a wide temperature range from 773 to 1773K are described in the first coordination shell and residual internal energy, respectively. The results reveal that during the simulated heating process, the properties undergo significant change at 1673K, which is in connection with the metal-nonmetal transition in the liquid. These findings coincide with the experimental observations of this thermodynamic phenomenon. Notably, the free energy of association that renders the system to this thermodynamic state is estimated.

Thermodynamics of π-π Interactions of Benzene and Phenol in Water.

The π–π interaction is a major driving force that stabilizes protein assemblies during protein folding. Recent studies have additionally demonstrated its involvement in the liquid–liquid phase separation (LLPS) of intrinsically disordered proteins (IDPs). As the participating residues in IDPs are exposed to water, π–π interactions for LLPS must be modeled in water, as opposed to the interactions that are often established at the hydrophobic domains of folded proteins. Thus, we investigated the association of free energies of benzene and phenol dimers in water by integrating van der Waals (vdW)-corrected density functional theory (DFT) and DFT in classical explicit solvents (DFT-CES). By comparing the vdW-corrected DFT and DFT-CES results with high-level wavefunction calculations and experimental solvation free energies, respectively, we established the quantitative credibility of these approaches, enabling a reliable prediction of the benzene and phenol dimer association free energies in water. We discovered that solvation influences dimer association free energies, but not significantly when no direct hydrogen-bond-type interaction exists between two monomeric units, which can be explained by the enthalpy–entropy compensation. Our comprehensive computational study of the solvation effect on π–π interactions in water could help us understand the molecular-level driving mechanism underlying the IDP phase behaviors.

Lipid-Mediated Association of the Slg1 Transmembrane Domains in Yeast Plasma Membranes.

Clustering of transmembrane proteins underlies a multitude of fundamental biological processes at the plasma membrane (PM) such as receptor activation, lateral domain formation, and mechanotransduction. The self-association of the respective transmembrane domains (TMDs) has also been suggested to be responsible for the micron-scaled patterns seen for integral membrane proteins in the budding yeast PM. However, the underlying interplay between the local lipid composition and the TMD identity is still not mechanistically understood. In this work, we combined coarse-grained molecular dynamics simulations of simplified bilayer systems with high-resolution live-cell microscopy to analyze the distribution of a representative helical yeast TMD from the PM sensor Slg1 within different lipid environments. In our simulations, we specifically evaluated the effects of acyl chain saturation and anionic lipid head groups on the association of two TMDs. We found that weak lipid-protein interactions significantly affect the configuration of TMD dimers and the free energy of association. Increased amounts of unsaturated phospholipids (PLs) strongly reduced the helix-helix interaction, while the presence of anionic phosphatidylserine (PS) hardly affected the dimer formation. We could experimentally confirm this surprising lack of effect of PS using the network factor, a mesoscopic measure of PM pattern formation in yeast cells. Simulations also showed that the formation of TMD dimers in turn increased the order parameter of the surrounding lipids and induced long-range perturbations in lipid organization. In summary, our results shed new light on the mechanisms of lipid-mediated dimerization of TMDs in complex lipid mixtures.

SPICA Force Field for Proteins and Peptides.

A coarse-grained (CG) model for peptides and proteins was developed as an extension of the Surface Property fItting Coarse grAined (SPICA) force field (FF). The model was designed to examine membrane proteins that are fully compatible with the lipid membranes of the SPICA FF. A preliminary version of this protein model was created using thermodynamic properties, including the surface tension and density in the SPICA (formerly called SDK) FF. In this study, we improved the CG protein model to facilitate molecular dynamics (MD) simulations with a reproduction of multiple properties from both experiments and all-atom (AA) simulations. An elastic network model was adopted to maintain the secondary structure within a single chain. The side-chain analogues reproduced the transfer free energy profiles across the lipid membrane and demonstrated reasonable association free energy (potential of mean force) in water compared to those from AA MD. A series of peptides/proteins adsorbed onto or penetrated into the membrane simulated by the CG MD correctly predicted the penetration depths and tilt angles of peripheral and transmembrane peptides/proteins as comparable to those in the orientations of proteins in membranes (OPM) database. In addition, the dimerization free energies of several transmembrane helices within a lipid bilayer were comparable to those from experimental estimation. Application studies on a series of membrane protein assemblies, scramblases, and poliovirus capsids demonstrated the good performance of the SPICA FF.

Reliable prediction of association (free) energies of supramolecular complexes with heavy main group elements - the HS13L benchmark set.

We introduce a set of 13 supramolecular complexes featuring diverse non-covalent interactions with heavy main group elements (Zn, As, Se, Te, Br, I), high charges (-2 up to +4), and large systems with up to 266 atoms (HS13L). The experimental Gibbs free energies of association cover the typical range (-1.9 to -9.2 kcal mol-1). An efficient automated multilevel theoretical workflow is applied for the determination of the respective minimum structures in solution by conformer ensemble generation with the CREST program at the semiempirical GFN2-xTB level. Subsequent refinement is performed with the r2SCAN-3c composite DFT method including thermostatistical corrections at the GFN2-xTB level and solvation contributions by COSMO-RS using the CENSO free energy ranking algorithm. Various density functional approximations in combination with three London dispersion correction schemes are assessed against "back-corrected" experimental association energies as well as accurate local coupled cluster reference values. Our protocol predicts association free energies with a mean absolute deviation of only 2 kcal mol-1 from the measured values. Thus, it is well suited to generate reference association free energies for assessing theoretical methods on realistically sized supramolecular complexes or to support experimental chemists. For specifically evaluating methods for calculating gas-phase association energies, we recommend using the provided accurate coupled cluster reference values. We propose to use this set as an extension of the S30L benchmark set [Sure et al., J. Chem. Theory Comput., 2015, 11, 3785-3801] with a special focus on the challenging computation of non-covalent interactions of heavy main group elements.

Corrections in the CHARMM36 Parametrization of Chloride Interactions with Proteins, Lipids, and Alkali Cations, and Extension to Other Halide Anions.

The nonpolarizable CHARMM force field is one of the most widely used energy functions for all-atom biomolecular simulations. Chloride is the only halide ion included in the latest version, CHARMM36m, and is used widely in simulation studies, often as an electrolyte ion but also as the biological substrate of transport proteins and enzymes. Here, we find that existing parameters systematically underestimate the interaction of Cl- with proteins and lipids. Accordingly, when examined in solution, little to no Cl-association can be observed with most components of the protein, including backbone, polar side chains and aromatic rings. The strength of the interaction with cationic side chains and with alkali ions is also incongruent with experimental measurements, specifically osmotic coefficients of concentrated solutions. Consistent with these findings, a 4-μs trajectory of the Cl--specific transport protein CLC-ec1 shows irreversible Cl- dissociation from the so-called Scen binding site, even in a 150 mM NaCl buffer. To correct for these deficiencies, we formulate a series of pair-specific Lennard-Jones parameters that override those resulting from the conventional Lorentz-Berthelot combination rules. These parameters, referred to as NBFIX, are systematically calibrated against available experimental data as well as ab initio geometry optimizations and energy evaluations, for a wide set of binary and ternary Cl- complexes with protein and lipid analogs and alkali cations. Analogously, we also formulate parameter sets for the other three biological halide ions, namely, fluoride, bromide, and iodide. The resulting parameters are used to calculate the potential of mean force defining the interaction of each anion and each of the protein and lipid analogues in bulk water, revealing association free energies in the range of -0.3 to -3.3 kcal/mol, with the F- complexes being the least stable. The NBFIX corrections also preserve the Cl- occupancy of CLC-ec1 in a second 4-μs trajectory. We posit that these optimized molecular-mechanics models provide a more realistic foundation for all-atom simulation studies of processes entailing changes in hydration, recognition, or transport of halide anions.

New insights into structural, electronic, reactivity, spectroscopic and pharmacological properties of Bergenin: Experimental, DFT calculations, MD and docking simulations

Bergenin is a polyphenol found in many medicinal plants that presents numerous activities, such as antiulcer, anti-inflammatory, antifungal, anticancer, antimicrobial, antidiabetic, antiviral and antioxidant, being, therefore, a research target nowadays. In the present study, bergenin, isolated from Endopleura uchi Huber Cuatrecasas plant, was studied through density functional theory (DFT) and time-dependent density functional theory (TD-DFT), at the B3LYP/6–311++G(2d,2p) and B3LYP-D3(BJ)/6–311+G(2d,p) levels, where the obtained optimized geometry, FT-IR and UV–Vis data were analyzed along with experimental data. The comparative IR studies, together with potential energy distribution (PED) calculation, enabled the assignment of the observed experimental IR bands, besides evaluating the existence of intermolecular H-bonds through dimers formation. The calculated electronic transitions are in good agreement with the experimental data, which allowed the characterization of the UV–Vis bands. HOMO-LUMO energy gaps, average local ionization energy (ALIE) surfaces and Fukui indices calculations were carried out, allowing to concisely evaluate the reactive sites of bergenin. Also, calculations of solvation free energies and free energies of association in water, methanol and ethanol were performed. Due to the know in vitro anti-inflammatory and anticancer activities presented by bergenin, molecular docking and molecular dynamic (MD) calculations were carried out in front of cyclooxygenases 1 and 2 and topoisomerases I and II, revealing good interactions of bergenin with the active site of the tested enzymes, justifying the experimental results found in literature.

Single-Point Hessian Calculations for Improved Vibrational Frequencies and Rigid-Rotor-Harmonic-Oscillator Thermodynamics.

The calculation of harmonic vibrational frequencies (HVF) to interpret infrared (IR) spectra and to convert molecular energies to free energies is one of the essential steps in computational chemistry. A prerequisite for accurate thermostatistics so far was to optimize the molecular input structures in order to avoid imaginary frequencies, which inevitably leads to changes in the geometry if different theoretical levels are applied for geometry optimization and frequency calculations. In this work, we propose a new method termed single-point Hessian (SPH) for the computation of HVF and thermodynamic contributions to the free energy within the modified rigid-rotor-harmonic-oscillator approximation for general nonequilibrium molecular geometries. The key ingredient is the application of a biasing potential given as Gaussian functions expressed with the root-mean-square-deviation (RMSD) in Cartesian space in order to retain the initial geometry. The theory derived herein is generally applicable to quantum mechanical (QM), semiempirical QM, and force-field (FF) methods. Besides a detailed description of the underlying theory including the important back-correction of the biased HVF, the SPH approach is tested for reaction paths, molecular dynamics snapshots of crambin, and supramolecular association free energies in comparison to high-level density functional theory (DFT) values. Furthermore, the effect on IR spectra is investigated for organic dimers and transition-metal complexes revealing improved spectra at low theoretical levels. On average, DFT reference free energies are better reproduced by the newly developed SPH scheme than by conventional calculations on freely optimized geometries or without any relaxation.

Wertheim's thermodynamic perturbation theory with double-bond association and its application to colloid-linker mixtures.

We extend Wertheim's thermodynamic perturbation theory to derive the association free energy of a multicomponent mixture for which double bonds can form between any two pairs of the molecules' arbitrary number of bonding sites. This generalization reduces in limiting cases to prior theories that restrict double bonding to at most one pair of sites per molecule. We apply the new theory to an associating mixture of colloidal particles ("colloids") and flexible chain molecules ("linkers"). The linkers have two functional end groups, each of which may bond to one of several sites on the colloids. Due to their flexibility, a significant fraction of linkers can "loop" with both ends bonding to sites on the same colloid instead of bridging sites on different colloids. We use the theory to show that the fraction of linkers in loops depends sensitively on the linker end-to-end distance relative to the colloid bonding-site distance, which suggests strategies for mitigating the loop formation that may otherwise hinder linker-mediated colloidal assembly.

Physical Bond Breaking in Associating Copolymer Liquids.

We combine ideas from polymer and glassy liquid physics to construct a new model for the bond-breaking time scale of attractive sticker groups in associating copolymer liquids that form transient networks. The activated event is argued to be a two-step process, involving first the release of the nonsticker dynamic caging constraints that defines the primary alpha relaxation, followed by attractive stickers surmounting an association free-energy barrier subject to a local frictional resistance which can be strongly affected by relaxation-diffusion decoupling. The ideas embedded in the model produce a consistent and good description of the bond-breaking time scale for diverse polymer chemistries and architectures as a function of temperature and fraction of sticky groups. Chemically sensible values for association free energies are deduced. In strong contrast, the existing phenomenological models are shown to incur qualitative failures.

Computational design of small molecular modulators of protein-protein interactions with a novel thermodynamic cycle: Allosteric inhibitors of HIV-1 integrase.

Targeting protein-protein interactions for therapeutic development involves designing small molecules to either disrupt or enhance a known PPI. For this purpose, it is necessary to compute reliably the effect of chemical modifications of small molecules on the protein-protein association free energy. Here we present results obtained using a novel thermodynamic free energy cycle, for the rational design of allosteric inhibitors of HIV-1 integrase (ALLINI) that act specifically in the early stage of the infection cycle. The new compounds can serve as molecular probes to dissect the multifunctional mechanisms of ALLINIs to inform the discovery of new allosteric inhibitors. The free energy protocol developed here can be more broadly applied to study quantitatively the effects of small molecules on modulating the strengths of protein-protein interactions.

Potentiality of carbon nanotube to encapsulate some alkylating agent anticancer drugs: a molecular simulation study

Encapsulation of chlorambucil, cyclophosphamide, and melphalan with (9,9) carbon nanotube was investigated in aqueous solution. The structures were modeled in gas phase applying density functional calculations. Then, solvation free energies and association free energies of considered structures in water were studied by Monte Carlo simulation and perturbation method. Outcomes of gas phase study revealed that all three drugs can encapsulate into carbon nanotube. Monte Carlo simulation results showed that electrostatic interactions play a crucial role in the intermolecular energies after encapsulation in aqueous media. It is found that among three drugs, solvation free energy of chlorambucil was increased after encapsulation. Moreover, solvation of carbon nanotube was enhanced after encapsulation of drugs which improve the pharmaceutical applications. Calculated association free energies indicated that chlorambucil–carbon nanotube was the only stable encapsulated drug in aqueous solution.

Computational Study of Association of Dihydroxybenzoic Acids in Solution: Testing the Molecular Self-Association Computational Methodology for Formation of Binary Systems

Already validated methodology for self-association in solutions were used to evaluate if this method could also be used in other studies regarding association in solution. Three isomeric dihydroxybenzoic acids were used to calculate Gibbs free energies of association for homodimers, heterotetramers and associates with solvent molecules by using DFT calculations in multiple environments and having different conformations.

Turn‐on fluorescent probe for Zn2+ ions based on thiazolidine derivative

In this study, simple on–off fluorescent/UV–visible (UV–Vis) probes were easily prepared using 2‐(2‐hydroxyphenyl)thiazolidine‐4‐carboxylic acid (Sen‐1) and/or 2‐(2‐hydroxy‐5‐nitrophenyl)thiazolidine‐4‐carboxylic acid (Sen‐2) for fast detection of Zn2+ ions. Their sensing properties towards common metal ions were investigated using UV–Vis and fluorescence spectroscopies. Sen‐1 and Sen‐2 displayed a significant change with the addition of Zn2+ ions in the UV–Vis spectra. The addition of Zn2+ ions induced a 104 nm bathochromic shift for Sen‐1. The binding ratio towards Zn2+ metal ions was determined to be 1:1 by using Job plot analysis and fluorescence spectroscopy. The association constant and free energy (ΔG) of Sen‐1 and Sen‐2 towards Zn2+ ions were calculated by the Benesi–Hildebrand equation. The limit of detection of Sen‐1 towards Zn2+ ions is 3.73 × 10−8 M, which is about 1/100 of the value recommended by the World Health Organization for drinking water. Sen‐1 was successfully applied to detect Zn2+ ions in water samples and the fluorescence test strip was prepared for visual detection of Zn2+ ions. Finally, the quantum chemical parameters of Sen‐1 and Sen‐2, such as highest occupied molecular orbital, lowest unoccupied molecular orbital, and chemical hardness, were investigated by the Becke, three‐parameter, Lee–Yang–Parr, Hartree–Fock, and M062x methods.