A theoretical study of receptor site models for trimethylammonium group interaction

Using pseudoreceptor modelling, we have derived a three-dimensional binding-site model for the structurally uncharacterised sweet-taste receptor. The receptor model was derived based on 17 sweet compounds of the isovanillyl class (4-methoxy-3-hydroxybenzyl) as the training set and consists of nine key amino-acid residues embedded in a hydrophobic receptor cavity. The underlying technology (software PrGen) allows for a dynamical treatment of the ligand–receptor complex (ligand equilibration and Monte-Carlo scanning of receptor space) as well as for receptor-mediated ligand alignment. Free energies of ligand binding are estimated based on ligand–receptor interactions, ligand desolvation energy, change of ligand internal energy and change of ligand entropy upon receptor binding.

Water permeation across various nitrogen-doped double-walled carbon nanotubes (N-DWCNT) has been studied with molecular dynamics simulations to better understand the influence of water-nanopore interaction on the water permeation rate. There exists a threshold interaction energy at around -34.1 kJ/mol. Over the threshold energy, the water flow through N-DWCNT decreases monotonically with the strengthening of the water-nanotube interaction. The effect on the water flow across the channel is found to be negligible when the interaction energy is weaker than the threshold. The water-nanotube interaction energy can be controlled by doping nitrogen atoms into the nanotube walls. Although the van der Waals interaction energy is much stronger than the electrostatic interaction energy, it is less sensitive to the proportion of doped nitrogen atoms. On the other hand, the electrostatic interaction energy weakens after the initial strengthening when the percentage of doped nitrogen atoms increases to ~25%. The doped nitrogen atoms make less influence on the overall electrostatic interaction energy when the proportion is over 25%, due to the repulsions among themselves. Thus, the monotonous strengthening of the van der Waals interaction energy seems to dominate the overall trend of the total interaction energy, whereas the change of the long-range electrostatic interaction energy characterizes the shape of the correlation curve, as the percentage of doped nitrogen atoms increases.

CONSPECTUS: In chemical and biological systems, various interactions that govern the chemical and physical properties of molecules, assembling phenomena, and electronic transport properties compete and control the microscopic structure of materials. The well-controlled manipulation of each component can allow researchers to design receptors or sensors, new molecular architectures, structures with novel morphology, and functional molecules or devices. In this Account, we describe the structures and electronic and spintronic properties of π-molecular systems that are important for controlling the architecture of a variety of carbon-based systems. Although DFT is an important tool for describing molecular interactions, the inability of DFT to accurately represent dispersion interactions has made it difficult to properly describe π-interactions. However, the recently developed dispersion corrections for DFT have allowed us to include these dispersion interactions cost-effectively. We have investigated noncovalent interactions of various π-systems including aromatic-π, aliphatic-π, and non-π systems based on dispersion-corrected DFT (DFT-D). In addition, we have addressed the validity of DFT-D compared with the complete basis set (CBS) limit values of coupled cluster theory with single, double, and perturbative triple excitations [CCSD(T)] and Møller-Plesset second order perturbation theory (MP2). The DFT-D methods are still unable to predict the correct ordering in binding energies within the benzene dimer and the cyclohexane dimer. Nevertheless, the overall DFT-D predicted binding energies are in reasonable agreement with the CCSD(T) results. In most cases, results using the B97-D3 method closely reproduce the CCSD(T) results with the optimized energy-fitting parameters. On the other hand, vdW-DF2 and PBE0-TS methods estimate the dispersion energies from the calculated electron density. In these approximations, the interaction energies around the equilibrium point are reasonably close to the CCSD(T) results but sometimes slightly deviate from them because interaction energies were not particularly optimized with parameters. Nevertheless, because the electron cloud deforms when neighboring atoms/ions induce an electric field, both vdW-DF2 and PBE0-TS seem to properly reproduce the resulting change of dispersion interaction. Thus, improvements are needed in both vdW-DF2 and PBE0-TS to better describe the interaction energies, while the B97-D3 method could benefit from the incorporation of polarization-driven energy changes that show highly anisotropic behavior. Although the current DFT-D methods need further improvement, DFT-D is very useful for computer-aided molecular design. We have used these newly developed DFT-D methods to calculate the interactions between graphene and DNA nucleobases. Using DFT-D, we describe the design of molecular receptors of π-systems, graphene based electronic devices, metalloporphyrin half-metal based spintronic devices as graphene nanoribbon (GNR) analogs, and graphene based molecular electronic devices for DNA sequencing. DFT-D has also helped us understand quantum phenomena in materials and devices of π-systems including graphene.

In the chemistry of metallic complexes, two important concepts have been used to rationalize the recognition and selectivity of a host by a guest: preorganization and complementarity. Both of these concepts stem from geometrical features. Less explored in the literature has been the interactional complementarity, where mainly the electronic factors in the intermolecular forces are involved. Because the charge transfer between a species rich in electrons (ligand) and another deficient in them (cation) is one of the main intermolecular factors that control the binding energies in metallic complexes, for such systems, we propose a simple model based on density functional theory. We define an interactional energy in which the geometrical energy changes are subtracted from the binding energies and just the electronic factors are taken into account. The model is tested for the complexation between bidentate and cyclic ligands and Ca, Pb, and Hg metal dications. The charge-transfer energy described by our model fits nicely with the interactional energy. Thus, when the geometrical changes do not contribute in a significant way to the complexation energy, the interactional energy is dominated by charge-transfer effects.

Chemical intuition suggests that anions and π-aromatic systems would repel each other. Typically, we think of cations as being attracted to electron-rich π-systems of aromatic rings, and the cation-π interaction, a well-established noncovalent interaction, plays an important role in nature. Therefore the anion-π interaction can be considered the opposite of the cation-π interaction. Computational studies of simple models of anion-π interactions have provided estimates of the factors that govern the binding geometry and the binding energy, leading to a general consensus about the nature of these interactions. In order to attract an anion, the charge distribution of the aromatic system has to be reversed, usually through the decoration of the aromatic systems with strongly electron-withdrawing groups. Researchers have little doubt about the existence of attractive anion-π interactions in the gas phase and in the solid state. The bonding energies assigned to anion-π interactions from quantum chemical calculations and gas phase experiments are significant and compare well with the values obtained for cation-π interactions. In solution, however, there are few examples of attractive anion-π interactions. In this Account, I describe several examples of neutral molecular receptors that bind anions in solution either solely through anion-π interactions or as a combination of anion-π interactions and hydrogen bonding. In the latter cases, the strength of the anion-π interaction is indirectly detected as a modulation of the stronger hydrogen bonding interaction (enforced proximity). The dissection of the energy contribution of the anion-π interaction to the overall binding is complex, which requires the use of appropriate reference systems. This Account gives an overview the experimental efforts to determine the binding energies that can be expected from anion-π interactions in solution with examples that center around the recognition of halides. The studies show that anion-π interactions also exist in solution, and the free energy of binding estimated for these attractive interactions is less than 1 kcal/mol for each substituted phenyl groups. The quantification of anion-π interactions in solution relies on the use of molecular recognition model systems; therefore researchers need to consider how the structure of the model system can alter the magnitude of the observed energy values. In addition, the recognition of anions in solution requires the use of salts (ion pairs) as precursors, which complicates the analysis of the titration data and the corresponding estimate of the binding strength. In solution, the weak binding energies suggest that anion-π interactions are not as significant for the selective or enhanced binding of anions but offer potential applications in catalysis and transport within functional synthetic and biological systems.

A hybrid quantum and molecular mechanical (QM/MM) free energy perturbation (FEP) method is implemented in the context of molecular dynamics (MD). The semiempirical quantum mechanical (QM) Hamiltonian (Austin Model 1) represents solute molecules, and the molecular mechanical (MM) CHARMM force field describes the water solvent. The QM/MM FEP method is used to calculate the free energy changes in aqueous solution for (1) a proton transfer from methanol to imidazole and (2) a hydride transfer from methoxide to nicotinamide. The QM/MM interaction energies between the solute and solvent arc calibrated to emulate the solute-solvent interaction energies determined at the Hartee-Fock 6-31G(d) level of ab initio theory. The free energy changes for the proton and hydride transfers are calculated to be 15.1 and {minus}6.3 kcal/mol, respectively, which compare favorably with the corresponding experimental values of 12.9 and {minus}7.4 kcal/mol. An estimate of the reliability of the calculations is obtained through the computation of the forward (15.1 and {minus}6.3 kcal/mol) and backward ({minus}14.1 and 9.1 kcal/mol)free energy changes. The reasonable correspondence between these two independent calculations suggests that adequate phase space sampling is obtained along the reaction pathways chosen to transform the proton and hydride systems between their respective reactant and product states.

Effect of various aryl substitutions on the interfacial interaction energy of graphene/conductive polymer nanocomposites

Background: Hypertension is a worldwide epidemic that has been recognized as the most leading global risk for mortality, with its prevalence associated with increased blood pressure, concomitant risks of cardiovascular and kidney diseases, and major commonality in individuals advanced in age. With the current treatment options for hypertension management, there is still a need to develop therapies that directly target receptors that aid in hypertension treatment. Methodology: The study focused on the in-silico profiling of the reported compounds from Areca catechu L. (fam. Arecaceae) towards the n-domain and c-domain angiotensin converting enzyme (ACE) receptor models. Bioisosteric replacement was used to create bioisosteres investigated for similar binding affinity. Results: Some A. catechu compounds exhibited favorable binding energies towards the n- and c-domain receptor models of ACE, binding in the same ACE ligand binding site as lisinopril, benazepril, and sampatrilat via similar interactions and amino acid residues. The majority of A. catechu compounds with favorable ACE binding energies belong to the phytochemical classes of flavonoids, polyphenols and phenolics, glycosides, and steroids. After in silico toxicity and pharmacokinetic profiling, the bioisosteres Leuco-DM02-39, Leuco-DM02-66, Leuco- DM05-60, Querc-DM09-63, and Querc-DM14-31 with binding energies higher than their parent compounds and comparable to lisinopril, benazepril, and sampatrilat were deemed the best. Conclusion: A. catechu compounds have the potential to target ACE n-domain and c-domain receptor models. Three leucocyanidin and two quercetin bioisosteres exhibited favorable binding to the n-domain and c-domain ACE receptor models and could be further optimized to derive a promising antihypertensive agent through ACE inhibition.

ANALYSIS OF OXYGEN EQUILIBRIA IN SYNTHETIC AND NATURAL MUTANT VALENCE HYBRID HEMOGLOBINS: IMPLICATIONS FOR MODELS OF HEME-HEME INTERACTION IN NORMAL HEMOGLOBIN

Molecular models of the M-H(2) binding sites of experimentally characterised amorphous vanadium hydrazide gels are studied computationally using gradient corrected density functional theory, to probe the coordination number of the vanadium in the material and the nature of the interaction between the metal and the H(2) molecules. The H(2) is found to bind to the vanadium through the Kubas interaction, and the first quantum theory of atoms-in-molecules analysis of this type of interaction is reported. Strong correlation is observed between the electron density at the H-H bond critical point and the M-H(2) interaction energy. Four coordinate models give the best reproduction of the experimental data, suggesting that the experimental sites are four coordinate. The V-H(2) interaction is shown to be greater when the non-hydrazine based ligand, THF, of the experimental system is altered to a poorer π-acceptor ligand. Upon altering the metal to Ti or Cr the M-H(2) interaction energy changes little but the number of H(2) which may be bound decreases from four (Ti) to two (Cr). It is proposed that changing the metal from V to Ti may increase the hydrogen storage capacity of the experimental system. A 9.9 wt% maximum storage capacity at the ideal binding enthalpy for room temperature performance is predicted when the Ti metal is combined with a coordination sphere containing 2 hydride ligands.

Computational study on interaction energy changes during double proton transfer process

Chapter 29. Receptor Modeling by Distance Geometry

On the basis of continuous medium theory, a model for evaluation of spectral shifts in solution has been developed in this work. The interaction energy between solute dipole and reaction field and the self-energy of the reaction field have been formulated through derivations. Applying the interaction energy expression together with the point dipole approximation to the case of spherical cavity produces new formulations of spectral shifts. The same expression of electrostatic free energy of the nonequilibrium state is achieved by integrating the change of the electrostatic free energy for a charging process. Moreover, generalized formulations evaluating spectral shifts have been established in the charge-potential notation, and the reduction of them to the point dipole case consistently leads to the same formulations of spectral shifts as those by interaction energy approach. Mutual supports provide convincing evidences for the reliability of the present results. In this work, attentions are particularly paid to the conclusion of zero self-energy of the reaction field, which is different from the previous theory. Reasoning and arguments are given on this point. From the present derivations, it is concluded that the spectral shifts of light absorption and emission were theoretically exaggerated in the past, in particular, by a factor of 2 for the spectral shift sum.

Stellar helium burning in other universes: A solution to the triple alpha fine-tuning problem

A general formulation of the free energy of interaction in cooperative ligand binding: application to hemoglobin.