Density functional theory investigation of cocaine water complexes

Twenty cocaine–water complexes were studied using density functional theory (DFT) B3LYP/6-311++G** level to understand their geometries, energies, vibrational frequencies, charge transfer and topological parameters. Among the 20 complexes, 12 are neutral and eight are protonated in the cocaine-water complexes. Based on the interaction energy, the protonated complexes are more stable than the neutral complexes. In both complexes, the most stable structure involves the hydrogen bond with water at nitrogen atom in the tropane ring and C?=?O groups in methyl ester. Carbonyl groups in benzoyl and methyl ester is the most reactive site in both forms and it is responsible for the stability order. The calculated topological results show that the interactions involved in the hydrogen bond are electrostatic dominant. Natural bond orbital (NBO) analysis confirms the presence of hydrogen bond and it supports the stability order. Atoms in molecules (AIM) and NBO analysis confirms the C-H?·?·?·?O hydrogen bonds formed between the cocaine-water complexes are blue shifted in nature.     

Theoretical investigations on the hydrogen bonding of nitrile isomers with H2O,HF, NH3 and H2S

The hydrogen bonds formed by the interaction of nitriles with water, hydrogen fluoride, ammonia and hydrogen sulphide have been studied using B3LYP and second-order Møller–Plesset perturbation (MP2) methods and 6-311+ + G(d,p) basis set. The energies and structures of 80 hydrogen-bonded complexes between nitriles and small molecules were examined systematically using B3LYP and MP2 procedure. Categorisation of the hydrogen bonds involved in the various complexes led to an ordering of hydrogen bond donor and acceptor abilities for some functional groups. The interaction energies have been corrected for the basis set superposition error using Boy's counterpoise correction method. The Morokuma energy decomposition analysis reveals that the strong interactions are due to the attractive contributions from the electrostatic (ES), polarisation (PL) and charge transfer (CT) components. The topological parameters, electron density and Laplacian of electron density show excellent correlation with the hydrogen bond length. Natural bond orbital (NBO) analysis has also been performed to study the CT from proton acceptor to the antibonding orbital of the H–Y bond in the proton donor part of complexes. The frequency analysis of C–H…Y bond in the complexes indicates the blue-shifting nature largely in case of sp² hybridised carbon atom.     

Theoretical studies on interaction of anticancer drugs (dacarbazine,procarbazine and triethylenemelamine) with normal (AT and GC) and mismatch (GG,CC, AA and TT) base pairs

This study is an attempt to gain a better understanding of the physicochemical interaction between novel anticancer drugs and DNA bases. We have employed quantum chemical tools to explore the interaction of a few anticancer drugs [namely procarbazine (PR), dacarbazine (DC) and triethylenemelamine (TR)] with isolated normal (GC and AT) and mismatch (AA, CC, GG and TT) base pairs. The molecular geometries, electronic structural stability, vibrational energies, chemical reactivity and other electronic properties were studied using MP2/6-311+G^**, B3LYP/6-311+G^** and M05-2X/6-311+G^** methods. The optimised geometries of the usual and mismatch base pairs are almost planar whereas the geometries of drug-interacting complexes deviate from planarity. The presence of steric hindrance and π-bond overlaps between C–C bonds in the complexes has distorted the planarity of the four- and five-member rings in the base pairs. Among the three drugs chosen, DC and PR bond well with normal and mismatch base pairs with large interaction energy. The electron density (ED) difference maps of the most stable GG–DC, GG–PR and GG–TR drug-interacting complexes show the information about sharing of ED and gain or loss of ED within the interacting molecules. The stabilisation energy of the charge transfer interaction between the relevant donor–acceptor orbital of GG–DC and GC–DC complexes has been found to be around 16 kcal/mol and GG–PR and GC–PR complexes has been found to be around 12 kcal/mol. But, for the GG–TR and GC–TR complexes, the stabilisation energy is found to be less than 6 kcal/mol. Moreover, the topological analysis of hydrogen bond network of DC and PR drug-interacting complexes have high electron and Laplacian density with structural stability at the bond critical points (BCPs), while compared TR drug-interacting complexes by atoms in molecules and natural bond orbital analysis. Finally, we may conclude that the drugs DC and PR are highly efficient drugs to target normal and mismatch base pair for control and inhibition of DNA replication.     

Competition between hydrogen bonds and halogen bonds in complexes of formamidine and hypohalous acids

Quantum chemical calculations have been per-formed for the complexes of formamidine (FA) and hypohalous acid (HOX, X = F, Cl, Br, I) to study their structures, properties, and competition of hydrogen bonds with halogen bonds. Two types of complexes are formed mainly through a hydrogen bond and a halogen bond, respectively, and the cyclic structure is more stable. For the F, Cl, and Br complexes, the hydrogen-bonded one is more stable than the halogen-bonded one, while the halogen-bonded structure is favorable for the I complexes. The associated H-O and X-O bonds are elongated and exhibit a red shift, whereas the distant ones are contracted and display a blue shift. The strength of hydrogen and halogen bonds is affected by F and Li substitutents and it was found that the latter tends to smooth differences in the strength of both types of interactions. The structures, properties, and interaction nature in these complexes have been understood with natural bond orbital (NBO) and atoms in molecules (AIM) theories.     

Ab Initio Quantum Mechanics Analysis of Imidazole C-H…O Water Hydrogen Bonding and a Molecular Mechanics Forcefield Correction

Abstract

While it is well established that classical hydrogen bonds play an important role in enzyme structure, function and dynamics, the role of weaker, but ‘activated’ C-H donor hydrogen bonds is poorly understood. The most important such case involves histidine which often plays a direct role in enzyme catalysis and possesses the most acidic C-H donor group of the standard amino acids. In the present study, we obtained optimized geometries and hydrogen bond interaction energies for C-H…O hydrogen bonded complexes between methane, ethylene, benzene, acetylene, and imidazole with water at the MP2-FC/6-31++G(2d,2p) and MP2-FC/aug-cc-pVDZ//MP2-FC/6-31++G(2d,2p) levels of theory. A strong linear relationship is obtained between the stability of the various hydrogen bonded complexes and both separation distances for H…0 and C—O. In general, these calculations indicate that C-H…0 interactions can be classified as hydrogen bonding interactions, albeit significantly weaker than the classical hydrogen bonds, but significantly stronger than just van der Waals interactions. For instance, while the electronic energy of stabilization at the MP2-FC/aug-cc-pVDZ//MP2-FC/6-31++G(2d,2p) level of theory of a water C-H…O water hydrogen bond is 4.36 kcal/mol more stable than the methane C-H…O water interaction, the water-water hydrogen bond is only 2.06 kcal/mol more stable than the imidazole C_e?H…O water hydrogen bond. Neglecting this latter hydrogen bonding interaction is obviously unacceptable. We next compare the potential energy surfaces for the imidazole C_e?H…O water and imidazole N_d?H…O hydrogen bonded complexes computed at the MP2/6-31++G(2d,2p) level of theory with the potential energy surface computed using the AMBER molecular mechanics program and forcefields. While the Weiner et al and Cornell et al AMBER forcefields reasonably account for the imidazole N-H…O water interaction, these forcefields do not adequately account for the imidazole C_e?H…O water hydrogen bond. A forcefield modification is offered that results in excellent agreement between the ab initio and molecular mechanics geometry and energy for this C-H…O hydrogen bonded complex.     

Interplay between halogen bonds and hydrogen bonds in OH/SH···HOX···HY (X = Cl, Br; Y = F, Cl, Br) complexes

The character of the cooperativity between the HOX···OH/SH halogen bond (XB) and the Y―H···(H)OX hydrogen bond (HB) in OH/SH···HOX···HY (X = Cl, Br; Y = F, Cl, Br) complexes has been investigated by means of second-order Møller?Plesset perturbation theory (MP2) calculations and “quantum theory of atoms in molecules” (QTAIM) studies. The geometries of the complexes have been determined from the most negative electrostatic potentials (V _S,min) and the most positive electrostatic potentials (V _S,max) on the electron density contours of the individual species. The greater the V _S,max values of HY, the larger the interaction energies of halogen-bonded HOX···OH/SH in the termolecular complexes, indicating that the ability of cooperative effect of hydrogen bond on halogen bond are determined by V _S,max of HY. The interaction energies, binding distances, infrared vibrational frequencies, and electron densities ρ at the BCPs of the hydrogen bonds and halogen bonds prove that there is positive cooperativity between these bonds. The potentiation of hydrogen bonds on halogen bonds is greater than that of halogen bonds on hydrogen bonds. QTAIM studies have shown that the halogen bonds and hydrogen bonds are closed-shell noncovalent interactions, and both have greater electrostatic character in the termolecular species compared with the bimolecular species.

The influence of hydrogen bonds on electron transfer rate in photosynthetic RCs

Hydrogen bonds formed between photosynthetic reaction centers (RCs) and their cofactors were shown to affect the efficacy of electron transfer. The mechanism of such influence is determined by sensitivity of hydrogen bonds to electron density rearrangements, which alter hydrogen bonds potential energy surface. Quantum chemistry calculations were carried out on a system consisting of a primary quinone Q(A), non-heme Fe(2+) ion and neighboring residues(.) The primary quinone forms two hydrogen bonds with its environment, one of which was shown to be highly sensitive to the Q(A) state. In the case of the reduced primary quinone two stable hydrogen bond proton positions were shown to exist on [Q(A)-His(M219)] hydrogen bond line, while there is only one stable proton position in the case of the oxidized primary quinone. Taking into account this fact and also the ability of proton to transfer between potential energy wells along a hydrogen bond, theoretical study of temperature dependence of hydrogen bond polarization was carried out. Current theory was successfully applied to interpret dark P(+)/Q(A)(-) recombination rate temperature dependence.     

Theoretical study of the discrimination between O(2) and CO by myoglobin

Combined quantum chemical and molecular mechanics geometry optimisations have been performed on myoglobin without or with O(2) or CO bound to the haem group. The results show that the distal histidine residue is protonated on the N(epsilon 2) atom and forms a hydrogen bond to the haem ligand both in the O(2) and the CO complexes. We have also re-refined the crystal structure of CO[bond]myoglobin by a combined quantum chemical and crystallographic refinement. Thereby, we probably obtain the most accurate available structure of the active site of this complex, showing a Fe[bond]C[bond]O angle of 171 degrees, and Fe[bond]C and C[bond]O bond lengths of 170-171 and 116-117 pm. The resulting structures have been used to calculate the strength of the hydrogen bond between the distal histidine residue and O(2) or CO in the protein. This amounts to 31-33 kJ/mol for O(2) and 2-3 kJ/mol for CO. The difference in hydrogen-bond strength is 21-22 kJ/mol when corrected for entropy effects. This is slightly larger than the observed discrimination between O(2) or CO by myoglobin, 17 kJ/mol. We have also estimated the strain of the active site inside the protein. It is 2-4 kJ/mol larger for the O(2) complex than for the CO complex, independent of which crystal structure the calculations are based on. Together, these results clearly show that myoglobin discriminates between O(2) and CO mainly by electrostatic interactions, rather than by steric strain.     

Contribution of intra- and intermolecular hydrogen bonds to the conformational stability of human lysozyme(,).

In globular proteins, there are intermolecular hydrogen bonds between protein and water molecules, and between water molecules, which are bound with the proteins, in addition to intramolecular hydrogen bonds. To estimate the contribution of these hydrogen bonds to the conformational stability of a protein, the thermodynamic parameters for denaturation and the crystal structures of five Thr to Val and five Thr to Ala mutant human lysozymes were determined. The denaturation Gibbs energy (DeltaG) of Thr to Val and Thr to Ala mutant proteins was changed from 4.0 to -5.6 kJ/mol and from 1.6 to -6.3 kJ/mol, respectively, compared with that of the wild-type protein. The contribution of hydrogen bonds to the stability (DeltaDeltaG(HB)) of the Thr and other mutant human lysozymes previously reported was extracted from the observed stability changes (DeltaDeltaG) with correction for changes in hydrophobicity and side chain conformational entropy between the wild-type and mutant structures. The estimation of the DeltaDeltaG(HB) values of all mutant proteins after removal of hydrogen bonds, including protein-water hydrogen bonds, indicates a favorable contribution of the intra- and intermolecular hydrogen bonds to the protein stability. The net contribution of an intramolecular hydrogen bond (DeltaG(HB[pp])), an intermolecular one between protein and ordered water molecules (DeltaG(HB[pw])), and an intermolecular one between ordered water molecules (DeltaG(HB[ww])) could be estimated to be 8. 5, 5.2, and 5.0 kJ/mol, respectively, for a 3 A long hydrogen bond. This result shows the different contributions to protein stability of intra- and intermolecular hydrogen bonds. The entropic cost due to the introduction of a water molecule (DeltaG(H)()2(O)) could be also estimated to be about 8 kJ/mol.     

Contribution of hydrogen bonds to the conformational stability of human lysozyme: calorimetry and X-ray analysis of six Ser --> Ala mutants.

To further examine the contribution of hydrogen bonds to the conformational stability of the human lysozyme, six Ser to Ala mutants were constructed. The thermodynamic parameters for denaturation of these six Ser mutant proteins were investigated by differential scanning calorimetry (DSC), and the crystal structures were determined by X-ray analysis. The denaturation Gibbs energy (DeltaG) of the Ser mutant proteins was changed from 2.0 to -5.7 kJ/mol, compared to that of the wild-type protein. With an analysis in which some factors that affected the stability due to mutation were considered, the contribution of hydrogen bonds to the stability (Delta DeltaGHB) was extracted on the basis of the structures of the mutant proteins. The results showed that hydrogen bonds between protein atoms and between a protein atom and a water bound with the protein molecule favorably contribute to the protein stability. The net contribution of one intramolecular hydrogen bond to protein stability (DeltaGHB) was 8.9 +/- 2.6 kJ/mol on average. However, the contribution to the protein stability of hydrogen bonds between a protein atom and a bound water molecule was smaller than that for a bond between protein atoms.     

Insight into the lithium/hydrogen bonding in (CH<Subscript>2</Subscript>)<Subscript>2</Subscript>X...LiY/HY (X: C=CH<Subscript>2</Subscript>, O,S; Y=F,Cl, Br) complexes

The nature of the lithium/hydrogen bonding between (CH₂)₂X(X: C=CH₂, O, S) and LiY/HY(Y=F, Cl, Br) have been theoretically investigated at MP2/6-311++G (d, p) level, using Bader’s “atoms in molecules (AIM)” theory and Weinhold’s “natural bond orbital (NBO)” methodology. The molecule formation density differences (MFDD) of the titled complexes are analyzed. Two kinds of geometries of the lithium/hydrogen bonded complexes are compared. As a whole, the nature of lithium bond and hydrogen bond are different. For the same electron donor and the same acceptor, lithium bond is stronger than hydrogen bond. For the same electron acceptor and different kind of donors, the interaction energies follows the n-type> π-type > pseudo-π-type order. For the same (CH₂)₂X, the interaction energy increases in the sequence of Y=F, Cl and Br for lithium bond systems while it decreases for hydrogen bond systems. Electron transfer plays an important role in the formation of lithium bond systems while it is less important in the hydrogen bond systems.     

On the significance of hydrogen bonds for the discrimination between CO and O2 by myoglobin

 Quantum chemical geometry optimisations have been performed on realistic models of the active site of myoglobin using density functional methods. The energy of the hydrogen bond between the distal histidine residue and CO or O₂ has been estimated to be 8 kJ/mol and 32 kJ/mol, respectively. This 24 kJ/mol energy difference accounts for most of the discrimination between CO and O₂ by myoglobin (about 17 kJ/mol). Thus, steric effects seem to be of minor importance for this discrimination. The Fe—C and C—O vibrational frequencies of CO-myoglobin have also been studied and the results indicate that CO forms hydrogen bonds to either the distal histidine residue or a water molecule during normal conditions. We have made several attempts to optimise structures with the deprotonated nitrogen atom of histidine directed towards CO. However, all such structures lead to unfavourable interactions between the histidine and CO, and to ν_CO frequencies higher than those observed experimentally. Received: 7 July 1998 / Accepted: 26 October 1998     

Modulating weak intramolecular interactions through the formation of beryllium bonds: complexes between squaric acid and BeH2

The electronic structure of the two most stable isomers of squaric acid and their complexes with BeH₂ were investigated at the B3LYP/6-311?+?G(3df,2p)// B3LYP/6-31?+?G(d,p) level of theory. Squaric acid forms rather strong beryllium bonds with BeH₂, with binding energies of the order of 60 kJ?mol^?1. The preferential sites for BeH₂ attachment are the carbonyl oxygen atoms, but the global minima of the potential energy surfaces of both EZ and ZZ isomers are extra-stabilized through the formation of a BeH···HO dihydrogen bond. More importantly, analysis of the electron density of these complexes shows the existence of significant cooperative effects between the beryllium bond and the dihydrogen bond, with both becoming significantly reinforced. The charge transfer involved in the formation of the beryllium bond induces a significant electron density redistribution within the squaric acid subunit, affecting not only the carbonyl group interacting with the BeH₂ moiety but significantly increasing the electron delocalization within the four membered ring. Accordingly the intrinsic properties of squaric acid become perturbed, as reflected in its ability to self-associate.

Interactions of anticancer drugs with usual and mismatch base pairs - density functional theory studies

The antitumor activity of a drug is associated with its molecular properties as well as its interactions with target molecules. The molecular structures of usual, mismatch base pairs and their drug (Hydroxyurea and 5-Fluorouracil) interacting complexes were studied using density functional theory methods. The two and three-body interaction energies have been used to analyze the influence of a drug on the stability of base pairs. The sharing of electron density between the interacting molecules is shown through electron density difference maps. The Atoms in Molecules theory and Natural Bond Orbital analysis have been performed to study the hydrogen bonds in the drug interacting complexes.     

A theoretical study on unusual intermolecular T-shaped X–H...π interactions between the singlet state HB=BH and HF, HCl, HCN or H2C2

The unusual T-shaped X–H...π hydrogen bonds are found between the B=B double bond of the singlet state HB=BH and the acid hydrogen of HF, HCl, HCN and H₂C₂ using MP2 and B3LYP methods at 6-311++G(2df,2p) and aug-cc-pVTZ levels. The binding energies follow the order of HB=BH...HF>HB=BH...HCl>HB=BH...HCN>HB=BH...H₂C₂. The hydrogen-bonded interactions in HB=BH...HX are found to be stronger than those in H₂C=CH₂...HX and OCB≡BCO...HX. The analyses of natural bond orbital (NBO) and the electron density shifts reveal that the nature of the T-shaped X–H...π hydrogen-bonded interaction is that much of the lost density from the π-orbital of B=B bond is shifted toward the hydrogen atom of the proton donor, leading to the electron density accumulation and the formation of the hydrogen bond. The atoms in molecules (AIM) theory have also been applied to characterize bond critical points and confirm that the B=B double bond can be a potential proton acceptor. The unusual T-shaped X–H...π hydrogen bonds are found between the B=B double bond of the singlet state HB=BH and the acid hydrogen of HF, HCl, HCN and H₂C₂     

Thermodynamics of water mediating protein-ligand interactions in cytochrome P450cam: a molecular dynamics study.

Ordered water molecules are observed by crystallography and nuclear magnetic resonance to mediate protein-ligand interactions. Here, we examine the energetics of hydrating cavities formed at protein-ligand interfaces using molecular dynamics simulations. The free energies of hydrating two cavities in the active site of two liganded complexes of cytochrome P450cam were calculated by multiconfigurational thermodynamic integration. The complex of cytochrome P450cam with 2-phenyl-imidazole contains a crystallographically well defined water molecule mediating hydrogen bonds between the protein and the inhibitor. We calculate that this water molecule is stabilized by a binding free energy of -11.6 +/- kJ/mol. The complex of cytochrome P450cam with its natural substrate, camphor, contains a cavity that is empty in the crystal structure although a water molecule in it could make a hydrogen bond to camphor. Here, solvation of this cavity is calculated to be unfavorable by +15.8 +/- 5.0 kJ/mol. The molecular dynamics simulations can thus distinguish a hydrated interfacial cavity from an empty one. They also provide support for the notion that protein-ligand complexes can accommodate empty interfacial cavities and that such cavities are likely to be unhydrated unless more than one hydrogen bond can be made to a water molecule in the cavity.     

The computational study of the γ-Fe2O3 nanoparticle as Carmustine drug delivery system: DFT approach

In the present study, it is attempted to scrutinize the properties of the maghemite nanoparticle as a Carmustine drug delivery system by means of the density functional theory calculations regarding their geometries, adsorption energies, vibrational frequencies, and topological features of the electron density. Based on the density functional theory results, it is found that the interaction between Carmustine drug molecule and maghemite nanoparticle is weak; so that, the adsorption of the Carmustine drug is typically physisorption. It is also found that the intermolecular hydrogen bonds between the drug and the nanoparticle play the significant role in the stability of the physisorption configurations. The nature of the intermolecular interactions has been explored by calculation of the electron densities and their Laplacian at the bond critical points using Atoms-in-Molecule theory. Moreover, natural bond orbital analysis indicates that the Carmustine molecule can be adsorbed on the nanoparticle surface with a charge transfer from the Carmustine drug to the nanoparticle.     

Hydrogen bonding interactions in noradrenaline-DMSO complexes: DFT and QTAIM studies of structure,properties and topology

The hydrogen bonding interactions between noradrenaline (NA) and DMSO were studied with density functional theory (DFT) regarding their geometries, energies, vibrational frequencies, and topological features of the electron density. The quantum theory of atoms in molecules (QTAIM) and the natural bond orbital (NBO) analyses were employed to elucidate the hydrogen bonding interaction characteristics in noradrenaline-DMSO complexes. The H-bonds involving the hydroxyls hydrogen in NA and the O atom in DMSO are dominant intermolecular H-bonds and are stronger than other H-bonds involving the methyl hydrogen of DMSO as a H-donor. The weak H-bonds also include a π H-bond which involves the benzene ring as a H-donor or H-acceptor. QTAIM identified the weak H-bonds formed between the methyl hydrogen of DMSO and the N atom in NA in some complexes (AB5, AB6 and AB7), which cannot be further confirmed by NBO and other methods, so there are probably no interactions between hydrogen and nitrogen atoms among these complexes. A good linear relationship between logarithmic electron density (lnρ _b ) at the bond critical point (BCP) and structural parameter (δR _H···Y) was found. The formations of new H-bonds in some complexes are helpful to strengthen the original intramolecular H-bond, this is attributed to the cooperativity of H-bonds in complexes and can be learned from the structure results and the NBO and QTAIM analyses. Analysis of various physically meaningful contributions arising from the energy decomposition procedures show that the orbital interactions of H-bond is predominant during the formation of the complex, moreover, both the hydrogen bonding interaction and the structural deformation are responsible for the stability of the complexes.     

Characteristics of beryllium bonds; a QTAIM study

The nature of beryllium bonds formed between BeX2 (X is H, F and Cl) and some Lewis bases have been investigated. The distribution of the Laplacian of electron density shows that there is a region of charge depletion around the Be atom, which, according to Laplacian complementary principal, can interact with a region of charge concentration of an atom in the base and form a beryllium bond. The molecular graphs of the investigated complexes indicate that beryllium in BeH2 and BeF2 can form “beryllium bonds” with O, N and P atoms but not with halogens. In addition, eight criteria based on QTAIM properties, including the values of electron density and its Laplacian at the BCP, penetration of beryllium and acceptor atom, charge, energy, volume and first atomic moment of beryllium atom, have been considered and compared with the corresponding ones in conventional hydrogen bonds. These bonds share many common features with very strong hydrogen bonds, however,some differences have also been observed.     

Molecular Docking Study of Beta-Glucosidase with Cellobiose,Cellotetraose and Cellotetriose

Beta-glucosidase (3.2.1.21) plays an essential role in the removal of non-reducing terminal glucosyl residues from glycosides. Recently, beta-glucosidase has been of interest for biomass conversion that acts in synergy with two other enzymes, endoglucanase and exo-glucanase. However, there is not much information available on the catalytic interactions of beta-glucosidase with its substrates. Thus, this study reports on the binding modes between beta-glucosidase from glycoside hydrolase family 1 namely BglB with cellobiose, cellotetraose and cellotetriose via molecular docking simulation. From the results, the binding affinities of BglB-cellobiose, BglB-cellotetraose, and BglB-cellotetriose complexes were reported to be -6.2kJ/mol , -5.68 kJ/mol and -5.63 kJ/mol, respectively. The detail interactions were also been investigated that revealed the key residues involved in forming hydrogen bonds (h-bond) with the substrates. These findings may provide valuable insigths in designing beta-glucosidase with higher cellobiose-hydrolyzing efficiency.