Enhanced pi ... pi interactions in alpha,beta-unsaturated carbonyls

High level ab initio calculations on complexes of benzene with acrolein and ethene reveal that pi ... pi interactions to electron deficient acrolein are remarkably similar to those found in the benzene dimer.     

Modelling of carbohydrate–aromatic interactions: <Emphasis Type="Italic">ab initio </Emphasis>energetics and force field performance

Summary Aromatic amino acid residues are often present in carbohydrate-binding sites of proteins. These binding sites are characterized by a placement of a carbohydrate moiety in a stacking orientation to an aromatic ring. This arrangement is an example of CH/π interactions. Ab initio interaction energies for 20 carbohydrate–aromatic complexes taken from 6 selected ultra-high resolution X-ray structures of glycosidases and carbohydrate-binding proteins were calculated. All interaction energies of a pyranose moiety with a side chain of an aromatic residue were calculated as attractive with interaction energy ranging from −2.8 to −12.3 kcal/mol as calculated at the MP2/6-311+G(d) level. Strong attractive interactions were observed for a wide range of orientations of carbohydrate and aromatic ring as present in selected X-ray structures. The most attractive interaction was associated with apparent combination of CH/π interactions and classical H-bonds. The failure of Hartree–Fock method (interaction energies from +1.0 to −6.9 kcal/mol) can be explained by a dispersion nature of a majority of the studied complexes. We also present a comparison of interaction energies calculated at the MP2 level with those calculated using molecular mechanics force fields (OPLS, GROMOS, CSFF/CHARMM, CHEAT/CHARMM, Glycam/AMBER, MM2 and MM3). For a majority of force fields there was a strong correlation with MP2 values. RMSD between MP2 and force field values were 1.0 for CSFF/CHARMM, 1.2 for Glycam/AMBER, 1.2 for GROMOS, 1.3 for MM3, 1.4 for MM2, 1.5 for OPLS and to 2.3 for CHEAT/CHARMM (in kcal/mol). These results show that molecular mechanics approximates interaction energies very well and support an application of molecular mechanics methods in the area of glycochemistry and glycobiology.     

CH/pi interactions in DNA and proteins. A theoretical study

A systematic study of the CH/pi interactions of methane with the purine and pyrimidine bases of nucleic acids and with the lateral chains of the four natural aromatic amino acids has been carried out for the first time. The MPWB1K/6-31+G(d,p) method has shown to be adequate for the study of these weak interactions in which dispersion forces play a main role. It has been shown that two different kinds of clusters exist, depending on whether one or two CH bonds point to the aromatic system. The latter one, which we have called bifurcated, is usually more stable. With regard to aromatic amino acids, our calculations agree with experimental data in the fact that tryptophan leads to the strongest interaction, while hystidine leads to the weakest one. In the case of nucleic acid bases, the differences in binding energies are not large. This is specially true for thymine and uracil, showing that these two bases have a similar acceptor character in CH/pi interactions.     

Experimental and theoretical determination of the accurate interaction energies in benzene-halomethane: the unique nature of the activated CH/pi interaction of haloalkanes

The CH/pi interaction energies between benzene and halomethanes (CH(2)Cl(2) and CHCl(3)) were accurately determined. Two-color ionization spectroscopy was applied to the benzene-CH(2)Cl(2) and -CHCl(3) clusters, and the binding energies in the neutral ground state, i.e. the CH/pi interaction energies in these model cluster systems, were precisely evaluated on the basis of the dissociation threshold measurements of the clusters in the cationic state and the ionization potential value of the bare molecule. The experimentally determined interaction energies were 3.8 +/- 0.2 and 5.2 +/- 0.2 kcal mol(-1) for benzene-CH(2)Cl(2) and -CHCl(3) respectively, and the remarkable enhancement of the CH/pi interaction energy with chlorine-substitution was quantitatively confirmed. The experimental interaction energies were well reproduced by the high-level ab initio calculations. The theoretical calculations clarified the unique nature of the activation of the CH/pi interaction by the chlorine-substitution.     

Saturated hydrocarbon-benzene complexes: theoretical study of cooperative CH/pi interactions

High-level ab initio calculations at the CCSD(T)/aug-cc-pVTZ//MP2/aug(d,p)-6-311G(d,p) level were employed to investigate the cooperative CH/pi effects between the pi face of benzene and several modeled saturated hydrocarbons, propane, isobutane, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentane, cyclooctane, and bicyclo[2.2.2]octane. In all cases, multiple C-H groups (2-4) are found to interact with the pi face of benzene, with one C-H group pointing close to the center of the benzene ring. The geometries of these complexes are governed predominantly by electrostatic interaction between the interacting systems. The calculated interaction energies (10-14 kJ mol(-1)) are 2-3 times larger than that of the prototypical methane-benzene complex. The trends of geometries, interaction energies, binding properties, as well as electron-density topological properties were analyzed. The calculated interaction energies correlate well with the polarizabilities of the hydrocarbons. AIM analysis confirms the hydrogen-bonded nature of the CH/pi interactions. Significant changes in proton chemical shift and stretching frequency (blue shift) are predicted for the ring C-H bond in these complexes.     

Beyond the benzene dimer: an investigation of the additivity of pi-pi interactions

The benzene dimer is the simplest prototype of pi-pi interactions and has been used to understand the fundamental physics of these interactions as they are observed in more complex systems. In biological systems, however, aromatic rings are rarely found in isolated pairs; thus, it is important to understand whether aromatic pairs remain a good model of pi-pi interactions in clusters. In this study, ab initio methods are used to compute the binding energies of several benzene trimers and tetramers, most of them in 1D stacked configurations. The two-body terms change only slightly relative to the dimer, and except for the cyclic trimer, the three- and four-body terms are negligible. This indicates that aromatic clusters do not feature any large nonadditive effects in their binding energies, and polarization effects in benzene clusters do not greatly change the binding that would be anticipated from unperturbed benzene-benzene interactions, at least for the 1D stacked systems considered. Three-body effects are larger for the cyclic trimer, but for all systems considered, the computed binding energies are within 10% of what would be estimated from benzene dimer energies at the same geometries.     

An atomistic model for simulations of nilotinib and nilotinib/kinase binding

Nilotinib is a novel anticancer drug, which specifically binds to the Abl kinase and blocks its signaling activity. In order to model the nilotinib/protein interactions, we have developed a molecular mechanics force field for nilotinib, consistent with the CHARMM force field for proteins and nucleic acids. Atomic charges were derived by utilizing a supermolecule ab initio approach. We considered the ab initio energies and geometries of a probe water molecule that interacts with nilotinib fragments at six different positions. We investigated both neutral and protonated states of nilotinib. The final rms deviation between the ab initio and the force field energies, averaged over both forms, was equal 0.2 kcal/mol. The model reproduces the ab initio geometry and flexibility of nilotinib. To apply the force field to nilotinib/Abl simulations, it is also necessary to determine the most likely protein and nilotinib protonation state when it binds to Abl. This task was carried out using molecular dynamics free energy simulations. The simulations indicate that nilotinib can interact with Abl in protonated and deprotonated forms, with the protonated form more favoured for the interaction. In the course of our calculations, we established that the His361, a titratable amino acid residue that mediates the interaction, prefers to be neutral. These insights and models should be of interest for drug design.     

Comparison of various types of hydrogen bonds involving aromatic amino acids

Ab initio calculations are used to compare the abilities of the aromatic groups of the Phe, Tyr, Trp, and His amino acids (modeled respectively by benzene, phenol, indole, and imidazole) to form H-bonds of three different types. Strongest of all are the conventional H-bonds (e.g., OH..O and OH..N). His forms the strongest such H-bond, followed by Tyr, and then by Trp. Whereas OH..phi bonds formed by the approach of a proton donor to the pi electron cloud above the aromatic system are somewhat weaker, they nonetheless represent an important class of stabilizing interactions. The strengths of H-bonds in this category follow the trend Trp > His > Tyr approximately Phe. CH.O interactions are weaker still, and only those involving His and Trp are strong enough to make significant contributions to protein structure. A protonated residue such as HisH(+) makes for a very powerful proton donor, such that even its CH..O H-bonds are stronger than the conventional H-bonds formed by neutral groups.     

Impact of the Chirality and Curvature of Carbon Nanostructures on Their Interaction with Aromatics and Amino Acids

Understanding noncovalent interactions on the surfaces of carbon nanostructures (CNSs) is of fundamental importance and also has implications in nano‐ and biotechnology. The interactions of aromatic compounds such as benzene, naphthalene, and aromatic amino acids with CNSs of varying diameter, chirality, and curvature were systematically explored by using density functional theory. Planar graphene exhibits stronger binding affinity than curved carbon nanotubes (CNTs), whereas zigzag CNTs appear to show stronger binding affinity than armchair CNTs. For hydrocarbons, there exist two competing modes, namely, π–π stacking interactions and CH ??? π interactions, which bring the aromatic motifs into parallel and perpendicular dispositions with respect to the CNSs, respectively. Our results reveal that π–π stacking interactions override CH ??? π interactions in such cases. However, in the case of aromatic amino acids, π–π interactions can exist simultaneously along with a range of other interactions, including CH ??? π. The polarizability and HOMO energy of the CNSs were found to be the key factors that determine the binding energies. The HOMO–LUMO energy gaps of the CNSs were found to be undisturbed by the noncovalent functionalization of the aromatic molecules.     

Cation-pi interactions with a model for the side chain of tryptophan: structures and absolute binding energies of alkali metal cation-indole complexes

Threshold collision-induced dissociation techniques are employed to determine bond dissociation energies (BDEs) of mono- and bis-complexes of alkali metal cations, Li+, Na+, K+, Rb+, and Cs+, with indole, C8H7N. The primary and lowest energy dissociation pathway in all cases is endothermic loss of an intact indole ligand. Sequential loss of a second indole ligand is observed at elevated energies for the bis-complexes. Density functional theory calculations at the B3LYP/6-31G level of theory are used to determine the structures, vibrational frequencies, and rotational constants of these complexes. Theoretical BDEs are determined from single point energy calculations at the MP2(full)/6-311+G(2d,2p) level using the B3LYP/6-31G* geometries. The agreement between theory and experiment is very good for all complexes except Li+ (C8H7N), where theory underestimates the strength of the binding. The trends in the BDEs of these alkali metal cation-indole complexes are compared with the analogous benzene and naphthalene complexes to examine the influence of the extended pi network and heteroatom on the strength of the cation-pi interaction. The Na+ and K+ binding affinities of benzene, phenol, and indole are also compared to those of the aromatic amino acids, phenylalanine, tyrosine, and tryptophan to elucidate the factors that contribute to the binding in complexes to the aromatic amino acids. The nature of the binding and trends in the BDEs of cation-pi complexes between alkali metal cations and benzene, phenol, and indole are examined to help understand nature's preference for engaging tryptophan over phenylalanine and tyrosine in cation-pi interactions in biological systems.     

Development of novel statistical potentials describing cation-pi interactions in proteins and comparison with semiempirical and quantum chemistry approaches

Novel statistical potentials derived from known protein structures are presented. They are designed to describe cation-pi and amino-pi interactions between a positively charged amino acid or an amino acid carrying a partially charged amino group and an aromatic moiety. These potentials are based on the propensity of residue types to be separated by a certain spatial distance or to have a given relative orientation. Several such potentials, describing different kinds of correlations between residue types, distances, and orientations, are derived and combined in a way that maximizes their information content and minimizes their redundancy. To test the ability of these potentials to describe cation-pi and amino-pi systems, we compare their energies with those computed with the CHARMM molecular mechanics force field and with quantum chemistry calculations at the Hartree-Fock level (HF) and at the second order of the M?ller-Plesset perturbation theory (MP2). The latter calculations are performed in the gas phase and in acetone, in order to mimic the average dielectric constant of protein environments. The energies computed with the best of our statistical potentials and with gas-phase HF or MP2 show correlation coefficients up to 0.96 when considering one side-chain degree of freedom in the statistical potentials and up to 0.94 when using a totally simplified model excluding all side-chain degrees of freedom. These potentials perform as well as, or better than, the CHARMM molecular mechanics force field that uses a much more detailed protein representation. The good performance of our cation-pi statistical potentials suggests their utility in protein structure and stability prediction and in protein design.     

Magnitude and orientation dependence of intermolecular interaction of perfluoropropane dimer studied by high-level ab initio calculations: comparison with propane dimer

Intermolecular interaction energies of 12 orientations of C(3)F(8) dimers were calculated with electron correlation correction by the second-order M?ller-Plesset perturbation method. The antiparallel C(2h) dimer has the largest interaction energy (-1.45 kcal/mol). Electron correlation correction increases the attraction considerably. Electrostatic energy is not large. Dispersion is mainly responsible for the attraction. Orientation dependence of the interaction energy of the C(3)F(8) dimer is substantially smaller than that of the C(3)H(8) dimer. The calculated interaction energy of the C(3)F(8) dimer at the potential minimum is 78% of that of the C(3)H(8) dimer (-1.85 kcal/mol), whereas the interaction energies of the CF(4) and C(2)F(6) dimers are larger than those of the CH(4) and C(2)H(6) dimers. The intermolecular separation in the C(3)F(8) dimer at the potential minimum is substantially larger than that in the C(3)H(8) dimer. The larger intermolecular separation due to the steric repulsion between fluorine atoms is the cause of the smaller interaction energy of the C(3)F(8) dimer at the potential minimum. The calculated intermolecular interaction energy potentials of the C(3)F(8) dimers using an all atom model OPLS-AA (OPLS all atom model) force field and a united atom model force field were compared with the ab initio calculations. Although the two force fields well reproduces the experimental vapor and liquid properties of perfluoroalkenes, the comparison shows that the united atom model underestimates the potential depth and orientation dependence of the interaction energy. The potentials obtained by the OPLS-AA force field are close to those obtained by the ab initio calculations.     

Affinity and enantioselectivity of Rifamycin SV towards low molecular weight compounds

Association of amino acids and some other low molecular weight compounds with rifamycin SV in water has been studied by ¹H NMR titrations. Rifamycin binds aromatic amino acids with pronounced enantioselectivity in favor of l-enantiomers and forms complexes with heterocyclic compounds but does not interact with simple benzene derivatives. Binding constants correlate with LUMO energies and hydrophobicities (expressed as log P values) of guest molecules indicating contributions to the binding free energy from aromatic stacking interactions with the naphthohydroquinone fragment of rifamycin SV and from hydrophobic interactions. Proposed mode of binding is supported by semiempirical calculations of structures of host–guest complexes.     

Nature of the water/aromatic parallel alignment interactions

The water/aromatic parallel alignment interactions are interactions where the water molecule or one of its O? H bonds is parallel to the aromatic ring plane. The calculated energies of the interactions are significant, up to ΔE_{CCSD(T)(limit)} = ?2.45 kcal mol^?1 at large horizontal displacement, out of benzene ring and CH bond region. These interactions are stronger than CH···O water/benzene interactions, but weaker than OH···π interactions. To investigate the nature of water/aromatic parallel alignment interactions, energy decomposition methods, symmetry‐adapted perturbation theory, and extended transition state‐natural orbitals for chemical valence (NOCV), were used. The calculations have shown that, for the complexes at large horizontal displacements, major contribution to interaction energy comes from electrostatic interactions between monomers, and for the complexes at small horizontal displacements, dispersion interactions are dominant binding force. The NOCV‐based analysis has shown that in structures with strong interaction energies charge transfer of the type π → σ*(O? H) between the monomers also exists. © 2014 Wiley Periodicals, Inc.     

Cation-π effects in the complexation of Na+ and K+ with Phe, Tyr, and Trp in the gas phase

Na⁺ and K⁺ gas-phase affinities of the three aromatic amino acids Phe, Tyr, and Trp were measured by the kinetic method. Na⁺ binds these amino acids much more strongly than K⁺, and for both metal ions the binding strength was found to follow the order Phe ≤ Tyr < Trp. Quantum chemical calculations by density functional theory (DFT) gave the same qualitative ordering, but suggested a somewhat larger Phe/Trp increment. These results are in acceptable agreement with predictions based on the binding of Na⁺ and K⁺ to the side chain model molecules benzene, phenol, and indole, and are also in reasonable agreement with the predictions from purely electrostatic calculations of the side-chain binding effects. The binding energies were compared with those to the aliphatic amino acids glycine and alanine. Binding to the aromatic amino acids was found to be stronger both experimentally and computationally, but the DFT calculations indicate substantially larger increments relative to alanine than shown by the experiments. Possible reasons for this difference are discussed. The metal ion binding energies show the same trends as the proton affinities.     

Amino acid analogues bind to carbon nanotube via π-π interactions: comparison of molecular mechanical and quantum mechanical calculations

Understanding the interaction between carbon nanotubes (CNTs) and biomolecules is essential to the CNT-based nanotechnology and biotechnology. Some recent experiments have suggested that the π-π stacking interactions between protein's aromatic residues and CNTs might play a key role in their binding, which raises interest in large scale modeling of protein-CNT complexes and associated π-π interactions at atomic detail. However, there is concern on the accuracy of classical fixed-charge molecular force fields due to their classical treatments and lack of polarizability. Here, we study the binding of three aromatic residue analogues (mimicking phenylalanine, tyrosine, and tryptophan) and benzene to a single-walled CNT, and compare the molecular mechanical (MM) calculations using three popular fixed-charge force fields (OPLSAA, AMBER, and CHARMM), with quantum mechanical (QM) calculations using the density-functional tight-binding method with the inclusion of dispersion correction (DFTB-D). Two typical configurations commonly found in π-π interactions are used, one with the aromatic rings parallel to the CNT surface (flat), and the other perpendicular (edge). Our calculations reveal that compared to the QM results the MM approaches can appropriately reproduce the strength of π-π interactions for both configurations, and more importantly, the energy difference between them, indicating that the various contributions to π-π interactions have been implicitly included in the van der Waals parameters of the standard MM force fields. Meanwhile, these MM models are less accurate in predicting the exact structural binding patterns (matching surface), meaning there are still rooms to be improved. In addition, we have provided a comprehensive and reliable QM picture for the π-π interactions of aromatic molecules with CNTs in gas phase, which might be used as a benchmark for future force field developments.     

Origin of attraction, magnitude, and directionality of interactions in benzene complexes with pyridinium cations

Geometries and interaction energies of benzene complexes with pyridine, pyridinium, N-methylpyridinium were studied by ab initio molecular orbital calculations. Estimated CCSD(T) interaction energies of the complexes at the basis set limit were -3.04, -14.77, and -9.36 kcal/mol, respectively. The interactions in the pyridinium and N-methylpyridinium complexes should be categorized into a cation/pi interaction, because the electrostatic and induction interactions greatly contribute to the attraction. On the other hand, the interaction in the pyridine complex is a pi/pi interaction. The dispersion interaction is mainly responsible for the attraction in the benzene-pyridine complex. Short-range interactions including charge-transfer interactions are not important for the attraction in the three complexes. The most stable pyridinium complex has a T-shaped structure, in which the N-H bond points toward the benzene, while the N-methylpyridinium complex prefers a slipped-parallel structure. The benzene-pyridine complex has two nearly isoenergetic (Slipped-parallel and T-shaped) structures.     

p-benzoquinone-benzene clusters as potential nanomechanical devices: a theoretical study

The equilibrium structures and binding energies of the benzene complexes of p-benzoquinones (PBQ) and its negatively charged anionic species (PBQ- and PBQ2-) have been investigated theoretically using second-order M?ller-Plesset calculations. While neutral p-benzoquinone-benzene clusters (PBQ-Bz) prefer to have a parallel displaced geometry (P-c), CH...pi interactions (T-shaped geometries) prevail in the di-anionic PBQ-benzene (PBQ2- -Bz) complexes (T-e2-). Studies on dianionic p-benzoquinone-benzene clusters showed that two nonbonded intermolecular interactions compete in the most stable conformation. One is H-bonding interaction (C-H...O type) between carbonyl oxygen of p-benzoquinone and one of the hydrogen atoms of benzene, and the other is a pi-H interaction between pi-electron cloud of PBQ2- and another hydrogen atom of benzene. Blueshifted H-bonds were observed in T-shaped clusters. The changes in the geometrical preference of PBQ-Bz complex upon addition of electrons would be useful in designing optimized molecular mechanical devices based on the edge-to-face and face-to-face aromatic interactions.