Computationally designed β‐turn foldamers of γ‐peptides based on 2‐(aminomethyl)cyclohexanecarboxylic acid

The γ‐peptide β‐turn structures have been designed computationally by the combination of chirospecific γ 2 , 3 ‐residues of 2‐(aminomethyl)cyclohexanecarboxylic acid (γAmc₆) with a cyclohexyl constraint on the C^α?C^β bond using density functional methods in water. The chirospecific γAmc₆ dipeptide with the (2S,3S)‐(2R,3R) configurations forms a stable turn structure in water, resembling a type II′ turn of α‐peptides, which can be used as a β‐turn motif in β‐hairpins of Ala‐based α‐peptides. The γAmc₆ dipeptide with homochiral (2S,3S)‐(2S,3S) configurations but different cyclohexyl puckerings shows the capability to be incorporated into one of two β‐turn motifs of gramicidin S. The overall structure of this gramicidin S analogue is quite similar to the native gramicidin S with the same patterns and geometries of hydrogen bonds. Our calculated results and the recently observed results may imply the wider applicability of chirospecific γ‐peptides with a cyclohexyl constraint on the backbone to form various peptide foldamers. © 2012 Wiley Periodicals, Inc. Biopolymers 97:1018–1025, 2012.     

Ion pair formation of phosphorylated amino acids and lysine and arginine side chains: A theoretical study

Protein phosphorylation is one of the major signal transduction mechanisms for controlling and regulating intracellular processes. Phosphorylation of specific hydroxylated amino acid side chains (Ser, Thr, Tyr) by protein kinases can activate numerous enzymes; this effect can be reversed by the action of protein phosphatases. Here we report ab initio (HF/6-31G* and Becke3LYP/6-31G*) and semiempirical (PM3) molecular orbital calculations pertinent to the ion pair formation of the phosphorylated amino acids with the basic side chains of Lys and Arg. Methyl-, ethyl-, and phenylphosphate, as well as methylamine and methylguanidinium were used as model compounds for the phosphorylated and basic amino acids, respectively. Phosphorylated amino acids were calculated as mono- and divalent anions. Our results indicate that the PSer/PThr ion pair interaction energies are stronger than those with PTyr. Moreover, the interaction energies with the amino group of Lys are generally more favorable than with the guanidinium group of Arg. The Lys amino groups form stable bifurcated hydrogen bonded structures; while the Arg guanidinium group can form a bidentate hydrogen bonded structure. Reasonable values for the interaction free energies in aqueous solution were obtained for some complexes by the inclusion of a solvent reaction field in the computation (PM3-SM3).     

Noncovalent interactions of nucleic acid bases with fullerene C60 and short carbon nanotube models: a dispersion-corrected DFT study

In the present work, we studied theoretically the noncovalent interaction of six nucleobases (NBs), namely uracil (U), thymine (T), cytosine (C), 5-methylcytosine (m⁵C), adenine (A) and guanine (G), with fullerene C₆₀ and two closed-end SWNT models of armchair (ANT) and zigzag (ZNT) chirality. The calculations were performed using the functional PBE of general gradient approximation, empirical dispersion correction by Grimme, in conjunction with the DNP double numerical basis set. For comparison purposes, two sets of calculations were carried out: the first one, under vacuum conditions, and the second one, in aqueous medium. We analysed the computed geometries and binding energies for NB + CNC complexes, the plots of HOMO and LUMO orbitals and the values of corresponding HOMO-LUMO gap energies. In particular, we found that under vacuum conditions, the interaction strength decreases in the order of G > m⁵C > A > C > T > U for C₆₀ and ZNT, and G > A > m⁵C > C > T > U for ANT. In aqueous medium, the binding energies decrease in the order of G > A > m⁵C > T > C > U for C₆₀ and ANT, and G > A > T > m⁵C > C > U for ZNT.     

Chiral dialkyl ditellurides: Conformation of chiral chromophore by circular dichroism and DFT calculation

The twisted structure of ditellurides, in a similar way as in other dichalcogenes, leads to different absorption of circularly polarized light by quasi‐enantiomeric chiral orbitals. Chiral optically active ditellurides are not common compounds and this phenomenon is not widely reported. As chiral ditellurides found an application in asymmetric synthesis, their molecular structure, understood as their conformation, became an important factor for understanding their reactivity. Until now there are few examples of chiral ditellurides known and their structure was not analyzed in details. This article presents the results of our most recent research on the structure of chiral ditellurides investigated by electronic circular spectroscopy (ECD) supported by quantum‐chemical calculation. This enables us to suggest a relationship between chirality of alkyl substituent and chirality (conformation) of ditelluride.     

Ion pair formation involving methylated lysine side chains: A theoretical study

Lysine residues with one, two, or three methyl groups substituted on the ?-nitrogen atom are found in many proteins. To evaluate the effect of the posttranslational methylation on ion-pair formation we have performed semiempirical and ab initio molecular orbital calculations, using the AMI method and the 6-31G^* basis set, respectively. Combinations of various methylated forms of methylamine and ethylamine with formate, acetate, and dimethyl phosphate were studied as model compounds. This approach allowed us to obtain information relevant to the interaction of the modified Lys residues with carboxylate groups of proteins, and the backbone of nucleic acids. We have found that the interaction energy decreases with an increasing number of methyl groups. Inclusion of a solvent reaction field in the semiempirical calculations gave reasonable values for the interaction energy in aqueous solution, when formate and acetate were the counterions. These studies suggest that, in addition to other factors, a weakening of ionic interactions contributes to the various physiological effects of lysine methylation. © 1994 John Wiley & Sons, Inc.     

A density functional theory study on the Ti/P binary cluster ions

Under the framework of density functional theory, an all-electron calculation on the geometrical structures and dissociation channels of Ti/P binary cluster ions has been carried out. The P₂, P₃ and P₄ structures are found to be the relatively stable units in these cluster ions. The lowest energy geometries of these Ti/P binary cluster ions may be constructed by bonding Ti, Ti₂, Ti₃ or Ti₄ unit with one or two relatively stable P₂, P₃ and P₄ units. The most possible dissociation channels of these Ti/P binary cluster ions are the detachment of P₂, P₃ or P₄ fragment. It is well consistent with the photodissociation experimental results.     

Stereochemical analysis of β‐keto sulfoxides by circular dichroism

Three β‐keto sulfoxides ( 1–3 ) were synthesized in enantiopure form and investigated by means of circular dichroism (CD) spectroscopy, both in electronic and vibrational range (ECD, VCD), in combination with quantum chemical calculations. For compound 2 , the X‐ray structure was available; thus, the ECD in the solid state was also considered to reveal the differences between the molecular species in both states. Despite the simplicity of all β‐keto sulfoxides under investigation (29 atoms), reproducing even the major spectral VCD features failed for two compounds, making the use of VCD not ideal to assign their absolute configuration in a reliable way. We demonstrated, however, that the use of ECD spectroscopy, both in solution and solid state, can easily, unambiguously, and without any complication simulate all bands by applying the standard protocol for calculations. This study may stimulate the debate on the need of the use of two chiroptical methods simultaneously in the determination of absolute configurations.     

Rate-limiting step of the iron porphyrin-catalysed oxidation of cyclohexane to adipic acid by DFT method

Deep understanding of the rate-limiting step in the oxidation process of cyclohexane to adipic acid would be useful for improving the activity of catalysts and selectivity of goal products. The rate-limiting step lied in high-valent species generation or C–H bond oxidation remains a controversial topic. In this paper, the mechanism of high-valent species generation and C–H bond activation was investigated by density functional theory. It was observed that the activation barrier of the high-valent species was lower than that of C–H bond activation; thereby the C–H bond oxidation was determined as the rate-limiting step. Calculated geometries and energies were in close agreement with the experimental observations. Furthermore, frontier molecular orbital analysis revealed that the C–H bond interacted with the high-valent species in different orientation and it showed how the reaction was manipulated and controlled by the iron–porphyrin in the catalytic process. Given the calculation correction, experiments were designed to reveal the rate-limiting step. This work provides a clear view of the debut on the rate-limiting step of the alkane oxidation. It should be a significant step forward for understanding the relationship between the porphyrin molecular structures and catalytic activity accurately and for predicting and designing high-activity catalysts.     

A DFT study on the second-order nonlinear optical properties of the plenary mixed-metal polyoxometalate

The redox and second-order nonlinear optical (NLO) properties of organic–inorganic hybrid polyoxoanions [LNbOEMe₃]^3 ? , [LNbOEPh₃]^3 ?  (L = α-{PW₁₁O₃₉}^7 ? , E = Si, Ge, Sn, Pb) are investigated by density functional theory method. The element substitution effects on the molecular nonlinear response have been analysed. The results show that the computed β₀ values depend on both E (E = Si < Ge < Sn < Pb) and the organic groups connected with E. For [LNbOEPh₃]^3 ?  (L = α-{PW₁₁O₃₉}^7 ? , E = Si, Ge, Sn, Pb), the analysis of major contributions to β₀ value suggests that the charge transfer from organic group to Keggin polyanion plays the key role in NLO response; the polyanion acts as a donor, whereas the organic group acts as an acceptor in [LNbOEPh₃]^3 ? . Our results show that this kind of organic–inorganic hybrid compound possesses larger molecular second-order polarisability and might be a potential NLO material.     

A study of the conformations of valinomycin in solution phase

Vibrational absorption and vibrational circular dichroism (VCD) spectra of valinomycin are measured, in different solvents, in the ester and amide carbonyl stretching regions. The influence of cations, namely Li(+), Na(+), K(+), and Cs(+), in methanol-d(4) solvent is also investigated. Ab initio quantum mechanical calculations using density functional theory and 6-31G* basis set are used to predict the absorption and VCD spectra. A bracelet-type structure for valinomycin that reproduces the experimental absorption and VCD spectra in inert solvents is identified. For the structure of valinomycin in polar solvents, a propeller-type structure was optimized, but further investigations are required to confirm this structure. A symmetric octahedral environment for the ester carbonyl groups in the valinomycin-K(+) complex is supported by the experimental VCD spectra. The results obtained in the present study demonstrate that even for large macrocyclic peptides, such as valinomycin, VCD can be used as an independent structural tool for the study of conformations in solution.     

Propensities of peptides containing the Asn‐Gly segment to form β‐turn and β‐hairpin structures

The propensities of peptides that contain the Asn‐Gly segment to form β‐turn and β‐hairpin structures were explored using the density functional methods and the implicit solvation model in CH₂Cl₂ and water. The populations of preferred β‐turn structures varied depending on the sequence and solvent polarity. In solution, β‐hairpin structures with βI′ turn motifs were most preferred for the heptapeptides containing the Asn‐Gly segment regardless of the sequence of the strands. These preferences in solution are consistent with the corresponding X‐ray structures. The sequence, H‐bond strengths, solvent polarity, and conformational flexibility appeared to interact to determine the preferred β‐hairpin structure of each heptapeptide, although the β‐turn segments played a role in promoting the formation of β‐hairpin structures and the β‐hairpin propensity varied. In the heptapeptides containing the Asn‐Gly segment, the β‐hairpin formation was enthalpically favored and entropically disfavored at 25°C in water. The calculated results for β‐turns and β‐hairpins containing the Asn‐Gly segment imply that these structural preferences may be useful for the design of bioactive macrocyclic peptides containing β‐hairpin mimics and the design of binding epitopes for protein–protein and protein–nucleic acid recognitions. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 653–664, 2016.     

Investigation of the intermolecular proton transfer in the supersystems adenine-methanol/ethanol/i-propanol: MP2 and DFT levels study

Twelve H-bonded supersystems constructed between the adenine tautomers and methanol, ethanol, and i-propanol were studied at the B3LYP and MP2 levels of theory using 6-311G(d,p) and 6-311++G(d,p) basis functions. The thermodynamic parameters of the complex formations were calculated in order to estimate the exact stability of the supersystems. It was proven that the calculated energy barriers of the alcohol-assisted proton transfers are about 60% lower than those of the intramolecular proton transfers in adenine found earlier (Gu and Leszczynski in J Phys Chem A 103:2744–2750, 1999). Figure H-bonded complex between i-propanol and adenine     

Kinetic and thermodynamic study of the substituent effect on the amino-Claisen rearrangement of para-substituted N-allyl-N-arylamine: a Hammett study via DFT

In order to find the susceptibility of the amino-Claisen rearrangement and the next proton shift reaction of N-allyl-N-arylamine to the substituent effects in the para position, the kinetic and thermodynamic parameters were calculated at the B3LYP level using the 6-31G^** basis set. The calculated activation energies for the rearrangements and proton shift reactions are close to 44.4 and 49.5 kcal mol^? 1, respectively. The transition states of the rearrangement with electron-donor substituents are more stable than those with electron-withdrawing substituent groups, but for the proton shift reaction, this situation is reversed (with the exception of fluorine atom for the rearrangement and fluorine and chlorine atoms for the proton shift reaction). Negative values for the activation entropy confirm the concerted mechanism for the amino-Claisen rearrangement and proton shift reaction. The Hammett ρ values of ? 2.4172 and ? 1.7791 are obtained for σ_p and σ^?  (enhanced sigma) in the amino-Claisen rearrangement, respectively. The correlation between log(k _X/k _H) and σ_p is weaker than that with σ^?  (enhanced sigma). A negative Hammett ρ value indicates that the electron-donating groups slightly increase the rate of amino-Claisen rearrangement. A positive Hammett ρ value (2.4921) for the proton shift reaction indicates that electron-withdrawing groups increase the rate of reaction.     

Probing the effect of nitro groups in nitramine based energetic molecules: a DFT and charge density study

The structure, electron density distribution, energetic and electrostatic properties of simple nitramine based energetic TMA, DMNA, MDA and TNA molecules were determined using density functional theory (B3LYP) with the 6-311G^** and aug-cc-pVDZ basis sets coupled with Bader's theory of atoms in molecules. In the NO₂ group substituted molecules, the N–N bond distance increases with the increase of NO₂ groups, whereas in C–N bonds, this effect is relatively less, and the distances are almost equal. The topological analysis of electron density reveals that the electron density ρ_bcp(r) of C–N and N–N bonds are significantly decreasing with the increase of NO₂ groups in the nitramine molecules. The Laplacian of electron density ▽²ρ_bcp(r) of N–NO₂ bonds [DMNA: ? 16.7 eÅ^? 5, MDA: ? 12.8 eÅ^? 5 and TNA: ? 7.9 eÅ^? 5] of the molecules are relatively less negative, and the values also decrease with the increase of NO₂ groups; this implies that the charge concentration decreases with the increase of NO₂ groups, which leads to weakening the N–N bonds of the molecules. The isosurface of molecular electrostatic potential displays high electronegative regions around the NO₂ groups. The oxygen balance OB₁₀₀ of the molecules increases as the number of NO₂ group increases in the molecules, in which, the TNA molecule having maximum OB₁₀₀ value [+7.89]. The band gap, heat of detonation, bond dissociation energy and charge imbalance are predominantly depends on the number of NO₂ group present in the molecule. The charge imbalance parameter (ν) has been calculated for all molecules, which reveals that TNA is a highly sensitive molecule, the corresponding ν value is 0.047.     

NMR chiral recognition of lipoic acid by cinchonidine CSA: A stereocenter beyond the organic function

Alpha-lipoic acid is a natural product that possesses distinct pharmacological properties. Lipoic acid is a short-chain fatty acid containing an asymmetric carbon at five bonds of distance to the organic function. Herein, we developed a nuclear magnetic resonance protocol to access the chiral recognition of lipoic acid in a simple and rapid procedure employing cinchonidine as a cheap chiral solvation agent in deuterated chloroform. To optimize this method, a statistical design of the experimental model was performed to produce a clear understanding of the optimal concentration, temperature, and molar ratio parameters. Based on the obtained spectra, the cinchonidine H₈-H₉ scalar coupling indicated a conformational preference in the chiral discrimination procedure. Density functional theory calculations established a proximity between the asymmetric center of lipoic acid and the aromatic moiety of cinchonidine, clarifying possible conformations in this ion-pair interaction. The described protocol demonstrates how far is far enough to chiral discrimination using a chiral solvation agent, expanding the method to compounds that contain a remote stereocenter.     

A theoretical study on H-bonding interactions in maleic acid: calculated 17O, 1H NMR parameters and QTAIM analysis

A theoretical study was carried out to examine intra- and intermolecular hydrogen bond (HB) properties in crystalline maleic acid (MA). We investigated geometries, ¹⁷O and ¹H nuclear magnetic resonance parameters of various MA clusters by means of M06 and B3LYP functionals using recently developed Jensen's polarisation-consistent basis sets, pcJ-n (n = 0, 1, 2, 3). Our results reveal that the calculated chemical shift isotropy, δ_iso, at the sites of ¹⁷O and ¹H nuclei depends markedly on the size of the basis set. Overall, convergence of the pcJ-n series is rather similar for both B3LYP and M06 functionals. An increase of δ_iso(¹⁷O) and δ_iso(¹H) in going from the pcJ-1 to the pcJ-3 basis set is a typical feature of the (MA)_1–3 clusters. The quantum theory of atoms in molecules (QTAIM) and energy decomposition analyses were also used to elucidate the interaction characteristics in the MA H-bonded network. According to QTAIM results obtained, it is concluded that strong HBs are more covalent in nature and weak HBs are mainly electrostatic interactions.     

Theoretical study of the infrared spectrum of 5-phenyl-1,3,4-oxadiazole-2-thiol by using DFT calculations

We have carried out a structural and vibrational study for 5-phenyl-1,3,4-oxadiazole-2-thiol by using the infrared (IR) spectrum and theoretical calculations. For a complete assignment of the compound IR spectrum, density functional theory calculations were combined with Pulay's scaled quantum mechanical force field methodology in order to fit the theoretical wavenumber values to the experimental ones. An agreement between theoretical and available experimental results was found. The theoretical vibrational calculations allowed us to obtain a set of scaled force constants fitting the observed wavenumbers. The results were then used to predict the Raman spectra, for which there are no experimental data. The nature of the benzyl and oxadiazole rings was studied by means of natural bond order and atoms in molecules theory calculations. In addition, the frontier molecular (highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO)) orbitals were analysed and compared with those calculated for the oxadiazole molecule.     

Tuning the properties of M(diimine)(dithiolate) complexes - The role of the metal and solvent effect. A combined experimental, DFT and TDDFT study

A combined experimental and DFT/TDDFT study on a series of seven M(diimine)(dithiolate) complexes of Group VIII metals has been performed. This analysis focuses mainly on three aspects: (a) the role of the metal, (b) the connection of NLO properties, through the intrinsic hyperpolarizability, with the slope of solvatochromic plots and (c) the effect of solvation on the valence orbitals of the complexes. Besides, the molecular and the electronic structure as well as the bonding scheme of these complexes are also explored. The three aforementioned aspects were not satisfactorily clarified in the literature up to now. Moreover, as it is proved, they possess a central role in the experimental design of the reactions in which these complexes take place or in the design of the synthesis of compounds with pre-required properties.     

Screening of the active site from water by the incoming ligand triggers catalysis and inhibition in serine proteases

The pKa of the catalytic His57 N(epsilon)H in the tetrahedral complex (TC) of chymotrypsin with trifluoromethyl ketone inhibitors is 4-5 units higher relative to the free enzyme (FE). Such stable TC's, formed with transition state (TS) analog inhibitors, are topologically similar to the catalytic TS. Thus, analysis of this pKa shift may shed light on the role of water solvation in the general base catalysis by histidine. We applied our QM/SCRF(VS) approach to study this shift. The method enables explicit quantum mechanical DFT calculations of large molecular clusters that simulate chemical reactions at the active site (AS) of water solvated enzymes. We derived an analytical expression for the pKa dependence on the degree of water exposure of the ionizable group, and on the total charge in the enzyme AS, Q(A) and Q(B), when the target ionizable functional group (His57 in this study) is in the acidic (A) and basic (B) forms, respectively. Q2(B) > Q2(A) both in the FE and in the TC of chymotrypsin. Therefore, water solvation decreases the relative stability of the protonated histidine in both. Ligand binding reduces the degree of water solvation of the imidazole ring, and consequently elevates the histidine pKa. Thus, the binding of the ligand plays a triggering role that switches on the cascade of catalytic reactions in serine proteases.