Aromatic-aromatic interactions in crystal structures of helical peptide scaffolds containing projecting phenylalanine residues

Aromatic-aromatic interactions between phenylalanine side chains in peptides have been probed by the structure determination in crystals of three peptides: Boc-Val-Ala-Phe-Aib-Val-Ala-Phe-Aib-OMe, I; Boc-Val-Ala-Phe-Aib-Val-Ala-Phe-Aib-Val-Ala-Phe-Aib-OMe, II; Boc-Aib-Ala-Phe-Aib-Phe-Ala-Val-Aib-OMe, III. X-ray diffraction studies reveal that all three peptides adopt helical conformations in the solid state with the Phe side chains projecting outward. Interhelix association in the crystals is promoted by Phe-Phe interactions. A total of 15 unique aromatic pairs have been characterized in the three independent crystal structures. In peptides I and II, the aromatic side chains lie on the same face of the helix at i/i + 4 positions resulting in both intrahelix and interhelix aromatic interactions. In peptide III, the Phe side chains are placed on the opposite faces of the helix, resulting in exclusive intermolecular aromatic interactions. The distances between the centroids of aromatic pair ranges from 5.11 to 6.86 A, while the distance of closest approach of ring carbon atoms ranges from 3.27 to 4.59 A. Examples of T-shaped and parallel-displaced arrangements of aromatic pairs are observed, in addition to several examples of inclined arrangements. The results support the view that the interaction potential for a pair of aromatic rings is relatively broad and rugged with several minima of similar energies, separated by small activation barriers.     

Van der Waals interactions in aromatic systems: structure and energetics of dimers and trimers of pyridine.

Full geometry optimizations at the dispersion-corrected DFT-BLYP level of theory were carried out for dimers and trimers of pyridine. The DFT-D interaction energies were checked against results from single-point SCS-MP2/aug-cc-pVTZ calculations. Three stacked structures and a planar H-bonded dimer were found to be very close in energy (interaction energies in the range from -3.4 to -4.0 kcal mol(-1)). Two T-shaped geometries are higher lying, by about 1 kcal mol(-1), which is explained by the more favorable electrostatic interactions in the stacked and H-bonded arrangements. The DFT-D approach has proved to be a reliable and efficient tool to explore the conformational space of aromatic van der Waals complexes and furthermore provides interaction energies with errors of less than 10-20 % of DeltaE. Comparisons with previous results obtained by using only partially optimized model geometries strongly indicate that unconstrained optimizations are mandatory in such weakly bonded low-symmetry systems.     

Stability of nucleic acid base pairs in organic solvents: molecular dynamics, molecular dynamics/quenching, and correlated ab initio study

The dynamic structure and potential energy surface of adenine...thymine and guanine...cytosine base pairs and their methylated analogues interacting with a small number (from 1 to 16 molecules) of organic solvents (methanol, dimethylsulfoxide, and chloroform) were investigated by various theoretical approaches starting from simple empirical methods employing the Cornell et al. force field to highly accurate ab initio quantum chemical calculations (MP2 and particularly CCSD(T) methods). After the simple molecular dynamics simulation, the molecular dynamics in combination with quenching technique was also used. The molecular dynamics simulations presented here have confirmed previous experimental and theoretical results from the bulk solvents showing that, whereas in chloroform the base pairs create hydrogen-bonded structures, in methanol, stacked structures are preferred. While methanol (like water) can stabilize the stacked structures of the base pairs by a higher number of hydrogen bonds than is possible in hydrogen-bonded pairs, the chloroform molecule lacks such a property, and the hydrogen-bonded structures are preferred in this solvent. The large volume of the dimethylsulfoxide molecule is an obstacle for the creation of very stable hydrogen-bonded and stacked systems, and a preference for T-shaped structures, especially for complexes of methylated adenine...thymine base pairs, was observed. These results provide clear evidence that the preference of either the stacked or the hydrogen-bonded structures of the base pairs in the solvent is not determined only by bulk properties or the solvent polarity but rather by specific interactions of the base pair with a small number of the solvent molecules. These conclusions obtained at the empirical level were verified also by high-level ab initio correlated calculations.     

The interaction of carbohydrates and amino acids with aromatic systems studied by density functional and semi-empirical molecular orbital calculations with dispersion corrections

Density functional theory (DFT-D) and semi-empirical (PM3-D) methods having an added dispersion correction have been used to study stabilising carbohydrate-aromatic and amino acid-aromatic interactions. The interaction energy for three simple sugars in different conformations with benzene, all give interaction energies close to 5 kcal mol(-1). Our original parameterization of PM3 (PM3-D) seriously overestimates this value, and has prompted a reparametrization which includes a modified core-core interaction term. With two additional parameters, the carbohydrate complexes, as well as the S22 data set, are well reproduced. The new PM3 scheme (PM3-D*) is found to describe the peptide bond-aromatic ring interactions accurately and, together with the DFT-D method, it is used to investigate the interaction of six amino acids with pyrene. Whilst the peptide backbone can adopt both stacked and T-shaped structures in the complexes with similar interaction energies, there is a preference for the unsaturated ring to adopt a stacked structure. Thus, peptides in which the latter interactions are maximised are likely to be the most effective for the functionalisation of carbon nanotubes.     

On the Reliability of the AMBER Force Field and its Empirical Dispersion Contribution for the Description of Noncovalent Complexes

The reliability of the AMBER force field is tested by comparing the total interaction energy and dispersion energy with the reference data obtained at the density functional theory–symmetry‐adapted perturbation treatment (DFT–SAPT)/aug‐cc‐pVDZ level. The comparison is made for 194 different geometries of noncovalent complexes (H‐bonded, stacked, mixed, and dispersion‐bound), at the equilibrium distances as well as at longer distances (up to a relative distance of two). The total interaction energies agree very well with the reference data and only the strength of H‐bonded complexes is slightly underestimated. In the case of dispersion energy, the overall agreement is even better, with the exception of the stacked aromatic systems, where the empirical dispersion energy is overestimated. The use of AMBER interaction energy and AMBER dispersion energy for different types of noncovalent complexes at equilibrium as well as at longer distances is thus justified, except for a few cases, such as the water molecule, where the dispersion energy is highly inaccurate.     

Aromatic chlorination of omega-phenylalkylamines and omega-phenylalkylamides in carbon tetrachloride and alpha,alpha,alpha-trifluorotoluene

The aromatic halogenation of simple alkylbenzenes with chlorine proceeds smoothly in acetic acid but is much less efficient in less polar solvents. By contrast chlorination of omega-phenylalkylamines, such as 3-phenylpropylamine, occurs readily in either acetic acid, carbon tetrachloride or alpha,alpha,alpha-trifluorotoluene, and in the latter solvents gives high proportions of ortho-chlorinated products. These effects are attributable to the involvement of N-chloroamines as reaction intermediates, with intramolecular delivery of the chlorine electrophile. Omega-phenylalkylamides, such as 3-phenylpropionamide, also easily undergo aromatic chlorination in carbon tetrachloride and alpha,alpha,alpha-trifluorotoluene. These reactions generally show a first-order dependence on the substrate concentration, but not on the amount of chlorine. With carbon tetrachloride, very similar reaction rates are observed with chlorine concentrations ranging from 0.1-1.5 M. In alpha,alpha,alpha-trifluorotoluene, the rates reach a plateau at a chlorine concentration of approximately 0.2 M. These features indicate that the reactions proceed via the formation of intermediates which evidence suggests may be the corresponding O-chloroimidates. Irrespective of the mechanistic details, the reactions are remarkably rapid, being faster than analogous reactions in acetic acid and three to four orders of magnitude more rapid than reactions of simple alkylbenzenes in carbon tetrachloride. Therefore, chlorination of the amines and amides may be accomplished without the need for highly polar solvents, added catalysts or large excesses of chlorine, which are often employed for electrophilic aromatic substitutions. Although the use of carbon tetrachloride is becoming increasingly impractical due to environmental concerns, the trifluorotoluene is a suitable alternative.     

Understanding of assembly phenomena by aromatic-aromatic interactions: benzene dimer and the substituted systems

Interactions involving aromatic rings are important in molecular/biomolecular assembly and engineering. As a consequence, there have been a number of investigations on dimers involving benzene or other substituted pi systems. In this Feature Article, we examine the relevance of the magnitudes of their attractive and repulsive interaction energy components in governing the geometries of several pi-pi systems. The geometries and the associated binding energies were evaluated at the complete basis set (CBS) limit of coupled cluster theory with singles, doubles, and perturbative triples excitations [CCSD(T)] using a least biased scheme for the given data set. The results for the benzene dimer indicate that the floppy T-shaped structure (center-to-center distance: 4.96 A, with an axial benzene off-centered above the facial benzene) is isoenergetic in zero-point-energy (ZPE) corrected binding energy (D0) to the displaced-stacked structure (vertical interplanar distance: 3.54 A). However, the T-shaped structure is likely to be slightly more stable (D0 approximately equal to 2.4-2.5 kcal/mol) if quadruple excitations are included in the coupled cluster calculations. The presence of substituents on the aromatic ring, irrespective of their electron withdrawing or donating nature, leads to an increase in the binding energy, and the displaced-stacked conformations are more stabilized than the T-shaped conformers. This explains the wide prevalence of displaced stacked structures in organic crystals. Despite that the dispersion energy is dominating, the substituent as well as the conformational effects are correlated to the electrostatic interaction. This electrostatic origin implies that the substituent effect would be reduced in polar solution, but important in apolar media, in particular, for assembling processes.     

一株红树内生真菌Penicillium sp.(ZZF29#)次级代谢产物分离与鉴定

研究了一株药用红树内生真菌Penicillium sp.(ZZF29#)的次级代谢产物。用硅胶柱层析、制备薄层层析和重结晶等方法,从该菌发酵液的乙酸乙酯相中分离获得8种单体化合物,运用现代波谱技术并与文献数据对照,鉴定其结构分别为:环(苯丙-丙)二肽(1)、环(苯丙-甘)二肽(2)、环(苯丙-苯丙)二肽(3)、环(苯丙-酪)二肽(4)、大黄素(5)、大黄素甲醚(6)、麦角甾醇(7)和过氧化麦角甾醇(8)。     

Conformation and Interaction of a D,L-alternating peptide with a bilayer membrane: x-ray reflectivity, CD, and FTIR spectroscopy.

Peptides with alternating amino acid configuration provide helical secondary structures that are especially known from the membrane channel and pore-forming gramicidin A. In analogy to this natural D,L-alternating pentadecapeptide, the potential of D,L-alternating peptides for membrane insertion is investigated using the model dodecamer peptide H-(Phe-Tyr)(5)-Trp-Trp-OH. This aromatic peptide is introduced as a novel pore-forming synthetic analogue of gramicidin A. It forms a well-organized homodimer similar to one of the gramicidin A transmembrane motifs. X-ray reflectivity measurements are performed on solid-supported peptide-lipid complexes to obtain information about the influence of the artificial dodecamer peptide on the bilayer parameters. In addition, Fourier-transform infrared (FTIR) and circular dichroism (CD) spectroscopic studies determine the conformational state of H-(Phe-Tyr)(5)-Trp-Trp-OH within the model membrane. Site-specific iodine labeling assists in determining the topology of the membrane-embedded peptide by pinpointing the position of the iodine label within the bilayers.     

H‐bonding and stacking interactions between chloroquine and temozolomide

The interactions between temozolomide and chloroquine were examined via Dispersion‐Corrected Density Functional Theory and MP2 methods. Chloroquine was considered in both its lowest energy structure and in a local minimum where its aromatic system and secondary amine group are free to interact directly with temozolomide. The accessibility of these two components to intermolecular interaction makes the lowest energy dimer of this local monomer minimum competitive in total energy with that involving chloroquine's most stable monomer geometry. In either case, the most stable heterodimer places the aromatic ring systems of the two molecules parallel and directly above one another in a stacked geometry. Most of the local minima are also characterized by a stacked geometry as well. Comparison between B3LYP and B3LYP‐D binding energies confirms dispersion is a primary factor in stabilizing these structures. © 2016 Wiley Periodicals, Inc.     

On geometries of stacked and H-bonded nucleic acid base pairs determined at various DFT, MP2, and CCSD(T) levels up to the CCSD(T)/complete basis set limit level

The geometries and interaction energies of stacked and hydrogen-bonded uracil dimers and a stacked adeninecdots, three dots, centeredthymine pair were studied by means of high-level quantum chemical calculations. Specifically, standard as well as counterpoise-corrected optimizations were performed at second-order Moller-Plesset (MP2) and coupled cluster level of theory with single, double, and perturbative triple excitations [CCSD(T)] levels with various basis sets up to the complete basis set limit. The results can be summarized as follows: (i) standard geometry optimization with small basis set (e.g., 6-31G(*)) provides fairly reasonable intermolecular separation; (ii) geometry optimization with extended basis sets at the MP2 level underestimates the intermolecular distances compared to the reference CCSD(T) results, whereas the MP2/cc-pVTZ counterpoise-corrected optimization agrees well with the reference geometries and, therefore, is recommended as a next step for improving MP2/cc-pVTZ geometries; (iii) the stabilization energy of stacked nucleic acids base pairs depends considerably on the method used for geometry optimization, so the use of reliable geometries, such as counterpoise-corrected MP2/cc-pVTZ ones, is recommended; (iv) the density functional theory methods fail completely in locating the energy minima for stacked structures and when the geometries from MP2 calculations are used, the resulting stabilization energies are strongly underestimated; (v) the self-consistent charges-density functional tight binding method, with inclusion of the empirical dispersion energy, accurately reproduces interaction energies and geometries of dispersion-bonded (stacked) complexes; this method can thus be recommended for prescanning the potential energy surfaces of van der Waals complexes.     

Free energy surfaces for the interaction of D-glucose with planar aromatic groups in aqueous solution

Multidimensional potentials of mean force for the interactions in aqueous solution of both anomers of D-glucopyranose with two planar aromatic molecules, indole and para-methyl-phenol, have been calculated using molecular dynamics simulations with umbrella sampling and were subsequently used to estimate binding free energies. Indole and para-methyl-phenol serve as models for the side chains of the amino acids tryptophan and tyrosine, respectively. In all cases, a weak affinity between the glucose molecules and the flat aromatic surfaces was found. The global minimum for these interactions was found to be for the case when the pseudoplanar face of β-D-glucopyranose is stacked against the planar surfaces of the aromatic residues. The calculated binding free energies are in good agreement with both experiment and previous simulations. The multidimensional free energy maps suggest a mechanism that could lend kinetic stability to the complexes formed by sugars bound to sugar-binding proteins.     

分子连接性指数与溶液吸附自由能的相关性

测定了硅胶自四氯化碳中吸附脂肪醇及活性炭自水中吸附芳香化合物的吸附等温线, 等温线均可用Langmuir方程描述。利用Langmuir参数计算了各体系的吸附标准自由能变化。计算了各种吸附质的分子连接性指数。各种分子的分子连接性指数与吸附标准自由能变化间有相关性, 并给出了相关方程, 同时作了初步的讨论。     

Hydration and stability of nucleic acid bases and base pairs

Empirical, quantum chemical calculations and molecular dynamics simulations of the role of a solvent on tautomerism of nucleic acid bases and structure and properties of nucleic acid base pairs are summarized. Attention was paid to microhydrated (by one and two water molecules) complexes, for which structures found by scanning of empirical potential surfaces were recalculated at a correlated ab initio level. Additionally, isolated as well as mono- and dihydrated H-bonded, T-shaped and stacked structures of all possible nucleic acid base pairs were studied at the same theoretical levels. We demonstrate the strong influence of a solvent on the tautomeric equilibrium between the tautomers of bases and on the spatial arrangement of the bases in a base pair. The results provide clear evidence that the prevalence of either the stacked or hydrogen-bonded structures of the base pairs in the solvent is not determined only by its bulk properties, but rather by specific hydrophilic interactions of the base pair with a small number of solvent molecules.     

Theoretical investigation of histidine-tryptophan preferential interactions

Several histidine-tryptophan complexes (either stacked or T-shaped), derived from the crystal structures available in the Brookhaven Protein Data Bank, have been examined with molecular mechanics (MM), using the Tripos force field with Gasteiger-Hückel charges, whose trend was found to be analogous to the AMBER or CHARMM ones. The MM results were compared to the ab initio MP2 results, with and without counterpoise (CP) correction, previously obtained using extended basis sets on 5-methylimidazole and indole as model systems. MM seems to underestimate the interaction energy between the two monomers when compared to the uncorrected MP2 results, while the agreement is much better after including the CP correction at the MP2 level in all cases. MM was thus used to qualitatively analyse the dependence of the stacking energy on the ring rotation at a variable distance and ring centroid displacement for these systems, while keeping the rings in parallel planes. An analogous study was carried out for a T-shaped adduct. Received: 24 March 1998 / Accepted: 3 September 1998 / Published online: 1 February 1999     

Another role of proline: stabilization interactions in proteins and protein complexes concerning proline and tryptophane

Proline-tryptophan complexes derived from experimental structures are investigated by quantum chemical procedures known to properly describe the London dispersion energy. We study two geometrical arrangements: the "L-shaped", stabilized by an H-bond, and the "stacked-like", where the two residues are in parallel orientation without any H-bond. Interestingly, the interaction energies in both cases are comparable and very large ( approximately 7 kcal mol(-1)). The strength of stabilization in the stacked arrangement is rather surprising considering the fact that only one partner has an aromatic character. The interaction energy decomposition using the SAPT method further demonstrates the very important role of dispersion energy in such arrangement. To elucidate the structural features responsible for this unexpectedly large stabilization we examined the role of the nitrogen heteroatom and the importance of the cyclicity of the proline residue. We show that the electrostatic interaction due to the presence of the dipole, caused by the nitrogen heteroatom, contributes largely to the strength of the interaction. Nevertheless, the cyclic arrangement of proline, which allows for the largest amount of dispersive contact with the aromatic partner, also has a notable-effect. Geometry optimizations carried out for the "stacked-like" complexes show that the arrangements derived from protein structure are close to their gas phase optimum geometry, suggesting that the environment has only a minor effect on the geometry of the interaction. We conclude that the strength of proline non-covalent interactions, combined with this residue's rigidity, might be the explanation for its prominent role in protein stabilization and recognition processes.     

Effect of microhydration on the guanidinium···benzene interaction

The effect of microhydration on the interaction of guanidinium cation with benzene has been studied by employing ab initio calculations. Four different structural arrangements were considered for the guanidinium···benzene interaction to which up to six water molecules were added. T-shaped structures are usually the most stable, but as water molecules are included the energy differences with the parallel structures decrease, reaching a point where parallel complexes are even more stable than T-shaped ones. Therefore, the inclusion of water molecules promotes a change in the structure of the cation···π contact. The analysis reveals that these stability changes are more related with the structure of the hydrating water molecules than to a modulation of the cation···π interaction. Already with three water molecules, one water molecule in the T-shaped complex has to be located in the second solvation shell, whereas in parallel structures this occurs with four water molecules. As a consequence energy differences among structures decrease. The calculations show that the nature of the interaction is almost unaffected in T-shaped structures, whereas an important dispersion increment is observed in parallel ones, though its overall effect is small.     

Quantitative determination of intermolecular interactions with fluorinated aromatic rings

The chemical double mutant cycle approach has been used to investigate substituent effects on intermolecular interactions between aromatic rings and pentafluorophenyl pi-systems. The complexes have been characterised using 1H and 19F NMR titrations, X-ray crystal structures of model compounds and molecular mechanics calculations. In the molecular zipper system used for these experiments, H-bonds and the geometries of the interacting surfaces favour the approach of the edge of the aromatic ring with the face of the pentafluorophenyl pi-system. The interactions are generally repulsive and this repulsion increases with more electron-withdrawing substituents up to a limit of +2.2 kJ mol(-1), when the complex distorts to minimise the unfavourable interaction. Strongly electron-donating groups cause a change in the geometry of the aromatic interaction and attractive stacking interactions are found (-1.6 kJ mol(-1) for NMe2). These results are generally consistent with an electrostatic model: the polarisation of the pentafluorophenyl ring leads to a partial positive charge located at the centre and this leads to repulsive interactions with the positive charges on the protons on the edge of the aromatic ring; when the aromatic ring has a high pi-electron density there is a large electrostatic driving force in favour of the stacked geometry which places this pi-electron density over the centre of the positive charge on the pentafluorophenyl group.     

Ab initio calculations of structures and interaction energies of toluene dimers including CCSD(T) level electron correlation correction

The intermolecular interaction energy of the toluene dimer has been calculated with the ARS-F model (a model chemistry for the evaluation of intermolecular interaction energy between ARomatic Systems using Feller's method), which was formerly called as the AIMI model III. The CCSD(T) (coupled cluster calculations with single and double substitutions with noniterative triple excitations) interaction energy at the basis set limit has been estimated from the second-order Moller-Plesset perturbation interaction energy at the basis set limit obtained by Feller's method and the CCSD(T) correction term obtained using a medium-size basis set. The cross (C(2)) dimer has the largest (most negative) interaction energy (-4.08 kcal/mol). The antiparallel (C(2h)) and parallel (C(S)) dimers (-3.77 and -3.41 kcal/mol, respectively) are slightly less stable. The dispersion interaction is found to be the major source of attraction in the toluene dimer. The dispersion interaction mainly determines the relative stability of the stacked three dimers. The electrostatic interaction of the stacked three dimers is repulsive. Although the T-shaped and slipped-parallel benzene dimers are nearly isoenergetic, the stacked toluene dimers are substantially more stable than the T-shaped toluene dimer (-2.62 kcal/mol). The large dispersion interaction in the stacked toluene dimers is the cause of their enhanced stability.