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 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.     

Hairpin formation promoted by the heterochiral dinipecotic acid segment: A DFT study

Conformational preferences for the turn and β‐hairpin structures of Ala‐based peptides [Ac‐Ala_n‐(R)‐Nip‐(S)‐Nip‐Ala_n‐X (n = 0–2; X = NHMe or NMe₂)] containing nipecotic acid (Nip) residues were carried out using the density functional M06‐2X and the implicit solvation model SMD in CH₂Cl₂ and/or water. The turn structure of the (R)‐Nip‐(S)‐Nip segment with a C₁₀ H‐bond between two terminal groups was found to be most preferred (populated at 98.9%) in CH₂Cl₂; this structure is consistent with IR and ¹H NMR results. The stabilities of the β‐hairpins containing the (R)‐Nip‐(S)‐Nip segment as a turn motif relative to the extended structures increased with peptide sequence length. The relative strengths of the H‐bonds between the carbonyl oxygen and the amide hydrogen appeared to be responsible for stabilizing the turn and β‐hairpin structures in CH₂Cl₂. In addition, the (R)‐Nip‐(S)‐Nip segment exhibited the capability to be incorporated into one of the two β‐turn motifs of gramicidin S (GS). The structure of this GS derivative (GS‐Nip₂) was generally similar to the native peptide but was less hydrophobic and it is therefore expected to exhibit lower hemolytic activity; however, further experiments are needed to evaluate its antimicrobial activity. The structure of GS‐Nip₂ was somewhat more flexible than GS in solvents of higher polarity. Thus, our calculated results regarding the turn and β‐hairpin motifs of the (R)‐Nip‐(S)‐Nip segment indicate that this structure might be useful for the design of bioactive macrocyclic peptides containing β‐hairpin mimics as well as binding epitopes in protein–protein and protein–nucleic acid recognitions. © 2015 Wiley Periodicals, Inc. Biopolymers 103: 609–617, 2015.     

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.     

A theoretical study of zinc(II) interactions with amino acid models and peptide fragments

Density functional theory calculations have been employed to study the interaction between the Zn²⁺ ion and some standard amino acid models. The highest affinities towards the Zn²⁺ ion are predicted for serine, cysteine, and histidine. Relatively high affinities are reported also for proline and glutamate/aspartate residues. It was found that the zinc complexes with cysteine adopt a tetrahedral conformation. Conversely, complexes with one or two histidine moieties remain in an octahedral geometry, while those with three or more histidine groups adopt a square-planar geometry. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Application of bioisosterism in design of the semicarbazone derivatives as cruzain inhibitors: a theoretical and experimental study

A series of semicarbazone, thiosemicarbazone, and aminoguanidine derivatives were synthesized and tested as antitrypanosomal agents. The theoretical NMR of the compounds was calculated using molecular modeling techniques (density functional theory (DFT) calculations) and confirmed the formation of the compounds. The ability to inhibit cruzain and Trypanosoma cruzi epimastigote replication was evaluated. Cruzain inhibition ranged between 70 and 75% (100 μM), and IC₅₀ values observed in epimastigote forms of T. cruzi ranged from 20 to 140 μM. Furthermore, the compounds did not present cytotoxicity at concentrations up to 50 and 250 μM in MTT tests. Molecular modeling studies were conducted using DFT method (B3LYP functional and the basis set 6-311G(d,p)) to understand the activity of the compounds, corroborating the observed cruzain inhibitory activity. In docking studies, the obtained analogs showed good complementarity with cruzain active site. In addition, docking results are in accordance with the susceptibility of these analogs to nucleophilic attack of the catalytic Cys25. Taken together, this study shows that this class of compounds can be used as a prototype in the identification of new antichagasic drugs.     

Oxidative degradation of quinazoline in supercritical water: a combined ReaxFF and DFT study

ABSTRACT

Quinazoline (Qu) is a representative heterocyclic compound in chemical wastewater. In this work, the supercritical water oxidation of Qu is investigated using molecular dynamics simulations based on the ReaxFF reactive force field combined with density functional theory (DFT) method. The detailed reaction pathways, transformation routes of nitrogen element, and kinetic behaviours are systematically analyzed at the atomistic level. Simulation results show that the increment of temperature and O₂ molecule accelerates the reaction rate and facilitates the complete destruction of Qu. The pyrimidine ring in Qu can be attacked by the OH radical, O₂ molecule, and H₂O molecule, thereby causing three main pathways for the pyrimidine ring-opening reaction. The aromatic ring undergoes a ring rearrangement process and opens under the attack of active O₂ molecules. DFT calculations demonstrate that the supercritical water cluster can decrease the cracking energy of chemical bonds and accelerate the degradation rate of Qu. In addition, the transformation routes of nitrogen element during reaction are described. NH₃ is found to be the primary N-containing product after ring-opening reactions and is an intermediate for the production of N₂. Finally, the value of activation energy is obtained as 123.0?kJ/mol, which is reasonably consistent with the experimental results.     

Elucidation of the chromatographic enantiomer elution order for praziquantel: An experimental and theoretical assessment

In this work, we have studied both experimentally and theoretically the praziquantel (PZQ) chiral discrimination. According to the main results, the enantioseparation of PZQ was efficiently optimized by HPLC on the reverse phase from the Chiralpak IB column, which has cellulose tris (3,5-dimethylphenylcarbamate) (CDMPC) as a chiral selector. The thermodynamic and structural parameters obtained via density functional theory (DFT) calculations pointed out the chiral discrimination as well as the enantiomeric elution order of PZQ, thus elucidating the experimental data and validating our proposed method. Finally, the hydrogen bonds and π-π stacking interactions played a key role in the discrimination between the PZQ diastereomeric complexes formed.     

Structural properties of sH hydrate: a DFT study of anisotropy and equation of state

ABSTRACT

Structure-H (sH) hydrate is one of the canonical gas hydrates with significant potential applications and scarce characterised material properties despite the wide knowledge available on other gas hydrates. In this work we characterise some of the important physical properties of this hydrate at the atomistic level using Density Functional Theory. Two exchange-correlation functionals (revPBE and DRSLL) were used to simulate six sH hydrate systems encapsulating neohexane and different help gas molecules. The important role of dispersion forces is quantified. The density and isothermal bulk modulus of sH hydrate are higher when dispersion interactions are considered. The presence of those interactions imposes a direct relationship between the hydrate density and its bulk modulus, while their absence reveals the bulk modulus dependency on hydrogen bond density. Anisotropy is a distinguishing feature of this hydrate in distinction to nearly isotropic sI and sII hydrates. Structure-H hydrate experiences a compressional anisotropy in which the a-lattice and the c-lattice constants respond differently to applied pressure showing less compressibility along the c-axis. This compressional anisotropy was found dependant on the chemistry of help gas molecules. Taken together, these property characterisation results and analysis are a significant and novel contribution to the material physics of sH hydrates.     

Structure,energetics and properties of some molecules with potent anti-HIV activity: a theoretical study

Density functional theory (DFT; B3LYP) and Hartree–Fock (HF; 3-21G, 6-31G(d) and 6-311G(d,p)) calculations with complete geometry optimisations are carried out in the ground state on five 6-aminoquinolone derivatives, which have been proved to be highly effective in inhibiting HIV replication, to study their structures, energetics and HOMO–LUMO correlation with physiological action. The gas-phase calculations and single-point polarisable continuum model water-phase calculations show that the molecules are highly effective in inhibiting HIV replication, which is in excellent agreement with the experiment. Structural features, energies, charge densities and HOMO–LUMO correlation have been found to substantiate the experimental findings. Compound 4 (pyrazine) shows some special features in DFT calculations which are not found in HF calculations. In the present series, HF results are more reliable as expected.     

Conformational investigation of alpha,beta-dehydropeptides. XV: N-acetyl-alpha,beta-dehydroamino acid N 'N '-dimethylamides: conformational properties from infrared and theoretical studies.

The FTIR spectra were analysed in the region of the nu(s)(N-H), AI(C=O) and nu(s)(Calpha=Cbeta) bands for a series of Ac-DeltaXaa-NMe2, where DeltaXaa = DeltaAla, (Z)-DeltaAbu, (Z)-DeltaLeu, (Z)-DeltaPhe and DeltaVal, to determine a predominant solution conformation of these alpha,beta-dehydropeptide-related molecules. Measurements were taken in CCl4, DCM and MeCN solutions. In the same way, spectra of saturated analogues Ac-Xaa-NMe2, where Xaa = Ala, Abu, Leu, Phe and Val, were investigated. To help interpret the spectroscopic results, conformational maps were calculated by the B3LYP/6-31+G** method. Also, the relative energies of all conformers of the dehydro compounds in vacuo as well as in the studied solvents in addition to the theoretical IR frequencies of these conformers were calculated. For comparison, molecules of two saturated analogues, Ac-L-Ala-NMe2 and Ac-L-Phe-NMe2, were calculated in a similar way. Both unsaturated and saturated compounds, which have an aliphatic side chain, occur in CCl4 and DCM mainly as a mixture of extended conformers with the C5 H-bond and open conformers. As solvent polarity increases, participation of the open conformers also increases, and in MeCN, the model amides are almost exclusively in the open form, except Ac-DeltaAla-NMe2, which shows a small amount of the H-bonded conformer. Ac-DeltaAla-NMe2 and Ac-DeltaAbu-NMe2 have stronger C5 hydrogen bonds than those of their saturated counterparts. As the calculations indicate, the open conformation of the unsaturated amides is conformer H/F with phi, psi -44 +/- 5 degrees, 127 +/- 4 degrees. This is the second lowest in energy conformer in vacuo and in CCl4 and the lowest one in more polar solvents. The open conformation of Ac-L-Ala-NMe2 constitutes conformer C with phi, psi -101.5 degrees, 112.7 degrees. For Ac-DeltaAla-NMe2 and Ac-DeltaAbu-NMe2, FTIR also reveals the presence of a third conformer. Calculations indicate that is the semiextended conformer D with the N1-H1...N2 hydrogen bond/contact. In all solvents, Ac-L-Phe-NMe2 and Ac-(Z)-DeltaPhe-NMe2 show only the extended E and the open H/F, respectively. In both there is an amide/pi(Ph) interaction.     

Ab initio study of phenyl benzoate: structure,conformational analysis,dipole moment,IR and Raman vibrational spectra

The molecular structure (bond distances and angles), conformational properties, dipole moment and vibrational spectroscopic data (vibrational frequencies, IR and Raman intensities) of phenyl benzoate were calculated using Hartree–Fock (HF), density functional (DFT), and second order Møller–Plesset perturbation theory (MP2) with basis sets ranging from 6-31G* to 6-311++G**. The theoretical results are discussed mainly in terms of comparisons with available experimental data. For geometric data, good agreement between theory and experiment is obtained for the MP2, B3LYP and B3PW91 levels with basis sets including diffuse functions. The B3LYP/6-31+G* theory level estimates the shape of the experimental functions for phenyl torsion around the Ph–O and Ph–C bonds well, but reproduces the height of the rotational barriers poorly. The B3LYP/6-31+G* harmonic force constants were scaled by applying the scaled quantum mechanical force field (SQM) technique. The calculated vibrational spectra were interpreted and band assignments were reported. They are in excellent agreement with experimental IR and Raman spectra.Figure Calculated and experimental (GED) potential energy functions for torsional motion of phenyl benzoate relative to the minimum value. a The potential function for torsion about the O₃–C₄ bond. b The potential function for torsion about the C₂–C₁₀ bond.     

Structural and electronic properties of diazonium functionalized (4, 4) single walled carbon nanotube: an ab initio study

In this work, ab initio density functional theory (DFT) calculations are performed to study the structural and electronic properties of diazonium reagent functionalized (4, 4) single-walled carbon nanotube (SWCNT). We find the aryl group covalently bonds with SWCNT and prefers to be perpendicular to the side wall of nanotube. It has a rotational barrier of 0.35 eV around the formed aryl-tube bond axis and should be thermodynamically stable at room temperature. Additionally, new peaks appeared around the Fermi energy in the density of state (DOS) due to the weak band dispersion. Increasing of the coverage of the functional group will result in significant upshift of the Fermi level.     

Insights into a highly conserved network of hydrogen bonds in the agonist binding site of nicotinic acetylcholine receptors: A structural and theoretical study

Structural and theoretical studies on the geometrical features of a hydrogen‐bond network occurring in the binding site of nicotinic acetylcholine receptors (nAChRs) and composed of interconnected WxPD (Trp‐x‐Pro‐Asp) and SWyz (Ser‐Trp‐yz) sequences from loops A and B, respectively, have been carried out. Multiple sequence alignments using as template the sequence of the apoform of Aplysia californica acetylcholine binding protein (Ac‐AChBP) show the strict conservation of serine and tryptophan residues of the loop B SWyz sequence. Considering a sample of 19 high resolution AChBP structures, the strong conformational preferences of the key tryptophan residue has been pointing out, whatever the form, free or bounded, of AChBP. The geometry of the motif hydrogen‐bond network has been characterized through the analyses of seven distances. The robustness of the various hydrogen‐bond interactions is pointed out, the one involving the aspartate carboxylate group and the serine residue being the shortest of the network. The role of a cooperative effect involving a NH(His145)…OH (Ser142) hydrogen bond is highlighted. Density functional theory calculations on several simplified models based on the motif hydrogen‐bond network allow probing the importance of the various hydrogen‐bond interactions. The removal of the Ser142 hydroxyl group induces strong structural rearrangements, in agreement with the structural observations. Molecular electrostatic potential calculations on model systems highlight the importance of a cooperative effect in the whole hydrogen‐bond network. More precisely, the key role of the Ser142 hydroxyl group, involved in several hydrogen bonds, is underlined. Proteins 2014; 82:2303–2317. © 2014 Wiley Periodicals, Inc.     

Tuning the electronic and photophysical properties of platinum(II) complexes through ancillary ligand modification: a theoretical study

In this work, six Pt(II) complexes have been studied via density functional theory (DFT)/time-dependent DFT caculations to explore the influence of different ancillary ligand on electron structures, photophysical properties and radiative decay processes. Moreover, the self-consistent spin–orbit coupling TDDFT was used to calculate zero-field splitting, radiative rate and radiative lifetime to unveil the radiative deactivation processes for these complexes. The results indicated that [Pt(ppy)(ppz)] (ppy = 2-phenylpyridine and ppz = 5-(2-pyridyl)-pyrazole) has a higher radiative decay rate constant and a smaller nonradiative decayrate constant than that of [Pt(ppy)(acac)] (acac = acetylacetonate). Furthermore, complex 5, with dimesityboron added on the 3′-position of the pyrazole ring in [Pt(ppy)(ppz)], shows great potential to serve as an efficient blue-green light emitter in OLED.     

A theoretical study on the exciton circular dichroism of propeller‐like metal complexes of bipyridine and tripodal tris(2‐pyridylmethyl)amine derivatives

Time‐dependent density functional theory (TD‐DFT) has been employed to simulate the circular dichroism (CD) spectra of bipyridyl ruthenium(II) complexes as well as zinc(II) and copper(II) complexes containing tris(2‐pyridylmethyl)amine (TPA) derivatives. A qualitative model is used to account for the mechanism by which the bis‐ and tris‐bipyridine complexes (or analogous systems) exhibit exciton CD. The model is further used to predict the sign of the exciton CD bands. The predictions are in agreement with experiment and DFT calculations. A comprehensive analysis is presented of the subtle differences in the CD spectra of this series of related complexes. Chirality, 2011. © 2010 Wiley‐Liss, Inc.     

A combined theoretical and spectroscopic study of 4,6-di-O-acetyl-2,3-dideoxy-d-erythro-hex-2-enopyranosyl sulfamide: a novel glycosyl carbonic anhydrase IX inhibitor

The novel 4,6-di-O-acetyl-2,3-dideoxy-d-erythro-hex-2-enopyranosyl sulfamide, which exhibits selectivity for inhibiting isoform IX of carbonic anhydrase as overexpressed in many tumors, has been investigated from a combined theoretical and spectroscopic point of view. The conformational study of the compound shows that the α-anomeric form is more stable than the β-anomeric form from a thermodynamic point of view after including solvent effects. This fact suggests that the synthesis reaction could take place mainly under thermodynamic control as the main experimental product is the α-anomeric form of the sulfamide. Calculated α/β ratio is about 95:5, in excellent agreement with experimental data. Optimized geometries of the α-anomeric form agree quite well with crystallographic data. The inclusion of a solvent has negligible effects on the conformations. A detailed analysis of some geometric parameters shed light into the conformational behavior of the sulfamide in terms of both exo- and endo-anomeric effects and antiperiplanar relationships. Natural bond orbital calculations confirm those findings. Several intramolecular hydrogen bonds, characterized through the Atoms-in-Molecules theory, were found in the stable conformers. They, however, seem to play no relevant role in determining the relative stability of α conformers with respect to the β ones. Calculated ¹H and ¹³C NMR chemical shifts support previous findings concerning configuration and conformation assignments of the title sulfamide. The IR spectrum of the compound is recorded and reported for the first time and the assignment of some of the most important bands is accomplished with the aid of calculated harmonic vibrational frequencies.     

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.     

Studies on intramolecular hydrogen bonding between the pyridine nitrogen and the amide hydrogen of the peptide: synthesis and conformational analysis of tripeptides containing novel amino acids with a pyridine ring.

For the first time tripeptides, Z-AA(1)-Xaa-AA(3)-OMe (AA(1) and AA(3) = Gly or Aib, Xaa = 2Pmg and 2Pyg) were prepared containing alpha-methyl-alpha-(2-pyridyl)glycine (2Pmg) and alpha-(2-pyridyl)glycine (2Pyg) by solid-phase Ugi reaction. These results clearly indicate that for the preparation of tripeptides containing an amino acid with a pyridine ring, the solid-phase Ugi reaction is very useful.NMR analysis clarified that 2Pmg-containing tripeptides adopt a unique conformation with an intramolecular hydrogen bond between 2Pmg-NH and the pyridine nitrogen. However, in the case of Z-Gly-2Pyg-Gly-OMe, the intramolecular hydrogen bonding between 2Pyg-NH and the pyridine nitrogen was not observed, whereas Z-Aib-2Pyg-Aib-OMe adopts a unique conformation with an intramolecular hydrogen bond between 2Pyg-NH and a pyridine nitrogen. Conformational analysis of the tripeptides, Z-AA(1)-Xaa-AA(3)-OMe (AA(1), AA(3) = Gly or Aib, Xaa = alpha,alpha-di(2-pyridyl)glycine (2Dpy), alpha-phenyl-alpha-(2-pyridyl)glycine (2Ppg), 2Pmg and 2Pyg), clarified that when an alpha,alpha-disubstituted glycine with a 2-pyridyl group at an alpha-carbon atom is introduced into any peptide, an intramolecular hydrogen bond between a pyridine nitrogen and an amide proton is formed and conformational mobility of the peptide backbone is restricted.