Gibbs Free Energy Of Binding Research Articles

Interaction of Proteins with Polyelectrolytes: Comparison of Theory to Experiment.

We discuss recent investigations of the interaction of polyelectrolytes with proteins. In particular, we review our recent studies on the interaction of simple proteins such as human serum albumin (HSA) and lysozyme with linear polyelectrolytes, charged dendrimers, charged networks, and polyelectrolyte brushes. In all cases discussed here, we combined experimental work with molecular dynamics (MD) simulations and mean-field theories. In particular, isothermal titration calorimetry (ITC) has been employed to obtain the respective binding constants Kb and the Gibbs free energy of binding. MD simulations with explicit counterions but implicit water demonstrate that counterion release is the main driving force for the binding of proteins to strongly charged polyelectrolytes: patches of positive charges located on the surface of the protein become multivalent counterions of the polyelectrolyte, thereby releasing a number of counterions condensed on the polyelectrolyte. The binding Gibbs free energy due to counterion release is predicted to scale with the logarithm of the salt concentration in the system, which is verified by both simulations and experiment. In several cases, namely, for the interaction of proteins with linear polyelectrolytes and highly charged hydrophilic dendrimers, the binding constant could be calculated from simulations to very good approximation. This finding demonstrated that in these cases explicit hydration effects do not contribute to the Gibbs free energy of binding. The Gibbs free energy can also be used to predict the kinetics of protein uptake by microgels for a given system by applying dynamic density functional theory. The entire discussion demonstrates that the direct comparison of theory with experiments can lead to a full understanding of the interaction of proteins with charged polymers. Possible implications for applications, such as drug design, are discussed.

Development of a machine-learning model to predict Gibbs free energy of binding for protein-ligand complexes

The possibility of using the atomic coordinates of protein-ligand complexes to assess binding affinity has a beneficial impact in the early stages of drug development and design. From the computational view, the creation of reliable scoring functions is still an open problem in the simulation of biological systems, and the development of a new generation machine-learning model is an active research field. In this work, we propose a novel scoring function to predict Gibbs free energy of binding (ΔG) based on the crystallographic structure of complexes involving a protein and an active ligand. We made use of the energy terms available the AutoDock Vina scoring function and trained a novel function using the machine learning methods available in the program SAnDReS. We used a training set composed exclusively of high-resolution crystallographic structures for which the ΔG data was available. We describe here the methodology to develop a machine-learning model to predict binding affinity using the program SAnDReS. Statistical analysis of our machine-learning model indicated a superior performance when compared to the MolDock, Plants, AutoDock 4, and AutoDock Vina scoring functions. We expect that this new machine-learning model could improve drug design and development through the application of a reliable scoring function in the analysis virtual screening simulations.

Cyclic peptide nanocapsule as ion carrier for halides: a theoretical survey

In this work, the encapsulations of halide ions including F−, Cl−, and Br− by cyclic peptide nanocapsule as ion carrier (F−, Cl−, and Br− @(Ala4...Ala4)) were investigated using the dispersion corrected density functional theory (DFT) employing CAM-B3LYP functional and the 6–311 + G (d, p) basis set in the gas phase. The electronic binding energy (Ebind), binding enthalpy (Hbind), and binding Gibbs free energy (Gbind) for each anion were calculated and showed that the stability order of the complexes based on their calculated Ebind is F− > Cl− > Br− @(Ala4...Ala4). The calculated value of Gbind for F− @(Ala4...Ala4) was − 29.77 kcal/mol showing the formation of this complex is thermodynamically favorable while the formation of Br− @(Ala4...Ala4) is 14.35 kcal/mol which shows that the encapsulation of Br− is not possible. The calculated value of Gbind for Cl− @(Ala4...Ala4) was − 0.57 kcal/mol which shows that Cl− ion can be reversibly stored inside the nanocapsule. The NBO analysis was also performed to investigate the charge transfer between two cyclic peptides in the complexes and also between the anion and the nanocapsule. The NBO analysis showed that the strongest hydrogen bonds between two cyclic peptides are in the complex.

Two distinct DNA sequences recognized by transcription factors represent enthalpy and entropy optima.

Most transcription factors (TFs) can bind to a population of sequences closely related to a single optimal site. However, some TFs can bind to two distinct sequences that represent two local optima in the Gibbs free energy of binding (ΔG). To determine the molecular mechanism behind this effect, we solved the structures of human HOXB13 and CDX2 bound to their two optimal DNA sequences, CAATAAA and TCGTAAA. Thermodynamic analyses by isothermal titration calorimetry revealed that both sites were bound with similar ΔG. However, the interaction with the CAA sequence was driven by change in enthalpy (ΔH), whereas the TCG site was bound with similar affinity due to smaller loss of entropy (ΔS). This thermodynamic mechanism that leads to at least two local optima likely affects many macromolecular interactions, as ΔG depends on two partially independent variables ΔH and ΔS according to the central equation of thermodynamics, ΔG = ΔH - TΔS.

Molecular Docking Simulation of Neuraminidase Influenza A Subtype H1N1 with Potential Inhibitor of Disulfide Cyclic Peptide (DNY, NNY, LRL)

Oseltamivir resistance as an inhibitor of neuraminidase influenza A virus subtype H1N1 has been reported lately. Therefore, to solve this problem, several kinds of research has been conducted to design and discover disulfide cyclic peptide ligands through molecular docking method, to find the potential inhibitors for neuraminidase H1N1 which then can disturb the virus replication. This research was studied and evaluated the interaction of ligands toward enzyme using molecular docking simulation, which was performed on three disulfide cyclic peptide inhibitors (DNY, LRL, and NNT), along with oseltamivir and zanamivir as the standard ligands using MOE 2008.10 software. The docking simulation shows that all disulfide cyclic peptide ligands have lower Gibbs free binding energies (ΔGbinding) than the standard ligands, with DNY ligand has the lowest ΔGbinding at -7.8544 kcal/mol. Furthermore, these ligands were also had better molecular interactions with neuraminidase than the standards, owing by the hydrogen bonds that were formed during the docking simulation. In the end, we concluded that DNY, LRL and NNT ligands have the potential to be developed as the inhibitor of neuraminidase H1N1.

Nanoscale Dynamics and Energetics of Proteins and Protein-Nucleic Acid Complexes in Classical Molecular Dynamics Simulations.

The present article describes techniques for classical simulations of proteins and protein-nucleic acid complexes, revealing their dynamics and protein-substrate binding energies. The approach is based on classical atomistic molecular dynamics (MD) simulations of the experimentally determined structures of the complexes. MD simulations can provide dynamics of complexes in realistic solvents on microsecond timescales, and the free energy methods are able to provide Gibbs free energies of binding of substrates, such as nucleic acids, to proteins. The chapter describes methodologies for the preparation of computer models of biomolecular complexes and free energy perturbation methodology for evaluating Gibbs free energies of binding. The applications are illustrated with examples of snapshots of proteins and their complexes with nucleic acids, as well as the precise Gibbs free energies of binding.

Tuning Enzyme/α-Zr(IV) Phosphate Nanoplate Interactions via Chemical Modification of Glucose Oxidase.

Using glucose oxidase (GOx) and α-Zr(IV) phosphate nanoplates (α-ZrP) as a model system, a generally applicable approach to control enzyme-solid interactions via chemical modification of amino acid side chains of the enzyme is demonstrated. Net charge on GOx was systematically tuned by appending different amounts of polyamine to the protein surface to produce chemically modified GOx(n), where n is the net charge on the enzyme after the modification and ranged from -62 to +95 electrostatic units in the system. The binding of GOx(n) with α-ZrP nanosheets was studied by isothermal titration calorimetry (ITC) as well as by surface plasmon resonance (SPR) spectroscopy. Pristine GOx showed no affinity for the α-ZrP nanosheets, but GOx(n) where n ≥ -20 showed binding affinities exceeding (2.1 ± 0.6) × 106 M-1, resulting from the charge modification of the enzyme. A plot of GOx(n) charge vs Gibbs free energy of binding (ΔG) for n = +20 to n = +65 indicated an overall increase in favorable interaction between GOx(n) and α-ZrP nanosheets. However, ΔG is less dependent on the net charge for n > +45, as evidenced by the decrease in the slope as charge increased further. All modified enzyme samples and enzyme/α-ZrP complexes retained a significant amount of folding structure (examined by circular dichroism) as well as enzymatic activities. Thus, strong control over enzyme-nanosheet interactions via modulating the net charge of enzymes may find potential applications in biosensing and biocatalysis.

Affinity and path of binding xylopyranose unto E. coli xylose permease

Glucose transporters (GLUTs), expressed in all types of human cells, are responsible for the uptake of sugars as the primary energy source for the normal functions of good cells and for the abnormal growth of cancer cells. The E. coli xylose permease (XylE), a homologue of human GLUTs, has been investigated more thoroughly than other major facilitator proteins in the current literature. In this paper, we present a molecular dynamics (MD) study of an all-atom model system to elucidate the atomistic details and the free-energy landscape along the path of binding a xylopyranose (XYP) from the extracellular space to the inside of the transporter protein XylE. From the MD simulations, the Gibbs free energy of binding was found to be −4.4kcal/mol in agreement with the experimental value of −4.7kcal/mol. The accuracy of our study is further shown in the computed hydration energy of XYP of −14.6kcal/mol in comparison with the experimental data of −15.0kcal/mol. Along the binding path, the Gibbs free energy of the XYP-XylE complex first rises from zero in the dissociated state to approximately 4 kcal/mol in the transition state (when XylE slightly increases its opening toward the extracellular side to accommodate XYP) before dropping down to −9.0 kcal/mol in the bound state. These quantitative insights indicate the fast equilibration between the bound and the unbound states of XylE and XYP. They also serve as an atomistic-dynamic corroboration of the experimental conclusion that XylE is a high-affinity sugar transporter.

The Interaction of a New Schiff Base Ligand with Human Serum Albumin: Molecular Docking and Molecular Dynamics Simulation Studies

ABSTRACTThe interaction of a new heterocyclic Schiff base bearing pyridine and pyrimidine cycles, with human serum albumin (HSA) using molecular docking and molecular dynamics simulation methods was examined. Molecular docking studies showed that the ligand was bonded to the IB domain of the protein. It was found that there was one hydrogen bond interaction between HSA and the ligand. The standard Gibbs free energy for binding of the ligand to HSA was calculated as −9.63 kcal.mol−1. The results of the molecular dynamics simulation showed that the root mean square deviation (RMSD) of the non-liganded HSA and the HSA–ligand complex reached equilibration after 1000 ps. The study of the radius of gyration revealed that there was a conformational change when the HSA–ligand complex was formed. Finally, analyzing the RMS fluctuations (RMSF) suggested that the structure of the ligand binding site remained approximately rigid during the simulation.

Adsorption-Coupled Diffusion of Gold Nanoclusters within a Large-Pore Protein Crystal Scaffold.

Large-pore protein crystals (LPCs) are ordered biologically derived nanoporous materials exhibiting pore diameters greater than 8 nm. These substantial pores distinguish LPCs from typical nanoporous scaffolds, enabling engineered LPC materials to readily uptake, immobilize, and release macromolecular guests. In this study, macromolecular transport within an LPC environment was experimentally and computationally investigated by studying adsorption-coupled diffusion of Au25(glutathione)18 nanoclusters within a cross-linked LPC scaffold via time-lapse confocal microscopy, bulk equilibrium adsorption, and hindered diffusion simulation. Equilibrium adsorption data is congruent with a Langmuir adsorption model, exhibiting strong binding behavior between nanoclusters and the scaffold. The standard Gibbs free energy of binding is equivalent to -37.2 kJ/mol, and the maximum binding capacity of 1.25 × 103 mg/g corresponds to approximately 29 nanoclusters per LPC unit cell. The hindered diffusion model showed good agreement with experimental data, revealing a pore diffusion coefficient of 3.7 × 10-7 cm2/s under low nanocluster concentration. Furthermore, the model was sufficient to determine adsorption and desorption kinetic values for ka and kd equal to 13 cm3/mol·s and 1.7 × 10-7 s-1, respectively. At higher nanocluster concentrations, the simulated pore diffusion coefficient could be reduced by 3 orders of magnitude to 3.4 × 10-10 cm2/s due to the effects of pore occlusion. This study demonstrates a strategy to analyze adsorption-coupled diffusion data to better understand complex transport of fluorescent macromolecules into LPCs. This approach fits the observable fluorescence data to the key molecular details and will benefit downstream efforts to engineer LPC-based nanoporous materials.

Molecular engineering of the electronic, structural, and electrochemical properties of nanostructured 1-methyl-4-phenyl 1,2,4 triazolium-based [PhMTZ][X1–10] ionic liquids through anionic changing

In the present work, molecular engineering of the physicochemical characteristics of ion pairing in 1-methyl-4-phenyl 1,2,4 triazolium-based ionic liquids [PhMTZ][X] (X1–10 = CH3CO2 −, Cl−, NO3 −, CF3CO2 −, BF4 −, ClO4 −, N(CN)2 −, PF6 −, NTf2 −, and C(CN)3 −) are explored using at M06-2X/6–311++G(d,p) level. The binding Gibbs free energy of ion pairs are reevaluated using ab initio MP2 method and dispersion corrected M06-2X-D3, B2PLYP, B2PLYP-D, and mPW2PLYP-D functionals. Comparison of Gibbs free bottom electrodes (BEs) calculated by B2PLYP and B2PLYP-D functionals reveals that the contribution of dispersion energy to the total BEs vary from 9% for X1 to 17% for X = 10. Besides, the range of the dispersion contribution estimated by M06-2X-D3 functional is found to be 0.6% for X2 to 5% for X3. The Gibbs free BEs in solvent media, Gibbs free energy and enthalpy of formation, electrochemical windows, anodic and cathodic stability, volumetric and electron density properties, charge transfer values, and electrostatic maps are evaluated.

Cross-linked Pluronic-g-Polyacrylic acid microgel system for the controlled release of doxorubicin in pharmaceutical formulations

The binding of doxorubicin (DOX) to cross-linked Pluronic F127-g-PAA-EGDMA and L92-g-PAA-EGDMA microgels at different alpha (α) and salt concentrations was investigated using isothermal titration calorimetric (ITC), optical and scanning electron microscopic techniques (SEM). We seek to elucidate the mechanisms of interaction and the release of DOX from cross-linked microgels composed of Pluronic and poly(acrylic acid). The ITC results indicated a high binding affinity of DOX to the microgel, which is a function of salt concentrations due to the impact of electrostatic shielding on the DOX-binding process. Applying the polyelectrolyte theory allows the decoupling of the Gibbs free energy of binding that describes the role of non-electrostatic interaction of DOX and the microgel. The presence of DOX within the microgel resulted in the collapse of the microgel due to charge shielding, π–π interactions and self-association of polymer-bound DOX molecules. The diffusion of DOX through the microgel is controlled by the dissociation of COO−/DOX+ coupling pairs.

<i>In silico</i> Design of Phosphonic Arginine and Hydroxamic Acid Inhibitors of <i>Plasmodium falciparum</i> M17 Leucyl Aminopeptidase with Favorable Pharmacokinetic Profile

We virtually design here new subnanomolar range antimalarials, inhibitors of <i>plasmodium falciparum</i> M17 Aminopeptidase (<i>pf</i>A-M17), by means of structure-based molecular design. Complexation QSAR models were elaborated for two training sets (6 methylphosphonic acids (APP) resp. 13 Hydroxamic Acid derivatives (AHO): QSAR_APP. resp. QSAR_AHO) and a linear correlation was established between the computed Gibbs free energies of binding (GFE: DDG_com) and observed enzyme inhibition constants (K_i^exp) for each training set: QSAR_APP: pK_i^exp=−0.1665´DDG_com+7.9581, R²=0.97 resp. QSAR_AHO: pK_i^exp=−0.4626´DDG_com+8.1842, R²=0.98. The predictive power of the QSAR models was validated with 3D-QSAR pharmacophore generation (PH4): PH4_APP: pK_i^exp=0.99677´pK_i^pred– 0.00457, R²=0.99 resp. PH4_AHO: pK_i^exp =1.02016´pK_i^pred–0.10478, R²=0.99. Breakdown of computed <i>pf</i>A-M17:APPs resp. <i>pf</i>A-M17:AHOs interaction energy into each active site residue’s contribution provided additional helpful structural information to design new APP and AHO analogues in a consistent way. In a first step we designed a virtual library (VL_APP resp. VL_AHO) from P₁ and P’ ₁ substitutions to explore both S₁ and S’ ₁ pockets. Further the VLs screened with the 3D-QSAR PH4s and the K_i^pred of the best fit hits virtually evaluated with QSAR_APP resp. QSAR_AHO models. This approach combining use of molecular modeling, PH4 and <i>in silico</i> VL screening helpfully provided valuable structural information for the synthesis of novel pfA-M17 inhibitors.

Prebiotic RNA polymerisation: energetics of nucleotide adsorption and polymerisation on clay mineral surfaces.

We measured the binding energy and bonding parameters between model nucleotide functional groups and model clay mineral surfaces in solutions of acidic pH. We demonstrate that basal surfaces of clay minerals interact most strongly with nucleobases and show that the adsorption of the phosphate group to clay edges could facilitate polymerisation. Our results suggest that Al- and Fe-rich edge sites behave similarly in nucleotide polymerisation through change of the phosphodiester bond strength. We present an internally consistent set of thermodynamic parameters that represent the nucleotide-clay mineral system.

Solubility profiles, hydration and desolvation of curcumin complexed with γ-cyclodextrin and hydroxypropyl-γ-cyclodextrin

In this study, we investigated curcumin (CUR) solubility profiles and hydration/desolvation effects of this substance formulated with γ-cyclodextrin (γ-CD) and hydroxypropyl-γ-cyclodextrin (HP-γ-CD) excipients. The CUR/HP-γ-CD complex was found to be more stable in solution with the highest apparent stability constant for CUR/HP-γ-CD (Kc = 1.58*104 M−1) as the more soluble form in distilled water. The in silico calculations, including molecular docking, Monte Carlo (MC), and molecular dynamics (MD) simulations, indicated that water molecules play an important role in host-guest complexation mediating the CUR binding to cyclodextrins via hydrogen bond formations. The CUR hydration/desolvation effects contributed to the complex formation by elevating the CUR binding affinity to both CDs. The CUR/HP-γ-CD complex after the CUR hydration was determined with a minimal Gibbs free energy of binding (ΔGbind = −9.93 kcal*mol−1) due to the major hydrophobic (vdW) forces. Overall, the results of this study can aid a development of cyclodextrin-based drug delivery vectors, signifying the importance of water molecules during the formulation processes.

Studies on the binding ability of diclofenac sodium to cationic surfactants micelles in aqueous ethanol solutions

Binding of diclofenac sodium (DCF), a non-steroidal anti-inflammatory drug, to hexadecyltrimethylammonium bromide and tetradecyltrimethylammonium bromide micelles in water as well as in aqueous ethanol solutions (0.0, 1.0, 2.5, 5.0, 7.5, 10.0 %) has been studied using isothermal titration calorimetry (ITC), UV–visible spectroscopy, and dynamic light scattering (DLS) techniques. Calorimetric data indicate that DCF binds with both the surfactants in approx 1:1 stoichiometry with binding constant (K b; obtained from ITC measurements) of order of 104 M−1. For both surfactants, K b values increase and Gibbs free energy of binding (∆G 0) decreases with ethanol concentration. Although ethanol weakens the hydrophobic interactions between two reacting species, the electrostatic interactions being stronger result in an overall increase in binding constant. Calorimetric results have been compared with those obtained spectroscopically. Further size variation studies on micelles upon binding with DCF (using DLS) complement the results obtained from these two techniques.

Characterization, in Vivo Evaluation, and Molecular Modeling of Different Propofol–Cyclodextrin Complexes To Assess Their Drug Delivery Potential at the Blood–Brain Barrier Level

In this study, we investigated the ability of the general anesthetic propofol (PR) to form inclusion complexes with modified β-cyclodextrins, including sulfobutylether-β-cyclodextrin (SBEβCD) and hydroxypropyl-β-cyclodextrin (HPβCD). The PR/SBEβCD and PR/HPβCD complexes were prepared and characterized, and the blood-brain barrier (BBB) permeation potential of the formulated PR was examined in vivo for the purpose of controlled drug delivery. The PR/SBEβCD complex was found to be more stable in solution with a minimal degradation constant of 0.25 h-1, a t1/2 of 2.82 h, and a Kc of 5.19 × 103 M-1 and revealed higher BBB permeability rates compared with the reference substance (PR-LIPURO) considering the calculated brain-to-blood concentration ratio (logBB) values. Additionally, the diminished PR binding affinity to SBEβCD was confirmed in molecular dynamics simulations by a maximal Gibbs free energy of binding (ΔGbind = -18.44 kcal·mol-1), indicating the more rapid PR/SBEβCD dissociation. Overall, the results demonstrated that SBEβCD has the potential to be used as a prospective candidate for drug delivery vector development to improve the pharmacokinetic and pharmacodynamic properties of general anesthetic agents at the BBB level.

Interaction of vitamin B1 with bovine serum albumin investigation using vitamin B1-selective electrode: potentiometric and molecular modeling study

Vitamin B1 or thiamin is one of the B vitamins. All B vitamins help the body to convert food (carbohydrates) into fuel (glucose), which produces energy. The B vitamins are necessary for healthy skin, eyes, hair, and liver. It also could help the nervous system function properly, and is necessary for brain functions. Drug interactions with protein can affect the distribution of the drug and eliminate the drug in living systems. In this study, the binding of thiamine hydrochloride (vitamin B1) to bovine serum albumin (BSA) was evaluated using a new proposed vitamin B1 (thiamine)-selective membrane electrode under various experimental conditions, such as pH, ionic strength, and protein concentration; in addition molecular modeling was applied as well. The binding isotherms plotted based on potentiometric data and analyzed using the Wyman binding potential concept. The apparent binding constant was determined and used for the calculation of intrinsic Gibbs free energy of binding. According to the electrochemical and molecular docking results, it can be concluded that the hydrophobic interactions and hydrogen binding are major interactions between BSA and vitamin B1.

Geometries, interaction energies and complexation free energies of 18-crown-6 with neutral molecules

Although 18-crown-6 is renowned for its binding affinity to various metal and ammonium cations, the nature and strength of its binding with neutral guest molecules is relatively unexplored. Here we report a computational study of the host : guest geometries, interaction energies and Gibbs free energies of formation of 18-crown-6 with 49 neutral guest molecules in the gas phase, using the G4(MP2) composite method. Optimized geometries are in excellent agreement with those observed in crystals, with differences readily attributed to guest : guest interactions in the solid state. Host : guest interaction energies range from −13 to −103 kJ mol−1, and the estimated Gibbs free energies of binding at 298 K correlate with the observation (or not) of the complexes in crystals. The electrostatic, dispersion, polarization and repulsion components of the interaction energy have also been estimated using the recently described CE-B3LYP model energies, providing insight into the binding nature between 18C6 and neutral molecules.

Spectroscopic, Electrochemical, andIn SilicoCharacterization of Complex Formed between 2-Ferrocenylbenzoic Acid and DNA

We present the synthesis of 2-ferrocenylbenzoic acid (FcOH) and its electrochemical and spectroscopic characterization. FcOH was characterized for interaction with DNA using theoretical and experimental methods. UV-visible spectroscopy and cyclic voltammeter (CV) were used for the experimental account of FcOH-DNA complex. The experimental results showed that the FcOH interacts by electrostatic mode. The binding constant (Kb) and Gibbs free energy (ΔG) for the FcOH-DNA complex have been estimated as 5.3 × 104 M−1and −6.44 kcal/mol, respectively. The theoretical DNA binding of FcOH was studied with AutoDock molecular docking software. The docking studies yield good approximation with experimental data and explain the sites of binding.