Neetha Mohan

Comparison of aromatic NH···π, OH···π, and CH···π interactions of alanine using MP2, CCSD, and DFT methods.

A comparison of the performance of various density functional methods including long‐range corrected and dispersion corrected methods [MPW1PW91, B3LYP, B3PW91, B97‐D, B1B95, MPWB1K, M06‐2X, SVWN5, ωB97XD, long‐range correction (LC)‐ωPBE, and CAM‐B3LYP using 6‐31+G(d,p) basis set] in the study of CH···π, OH···π, and NH···π interactions were done using weak complexes of neutral (A) and cationic (A+) forms of alanine with benzene by taking the Møller–Plesset (MP2)/6‐31+G(d,p) results as the reference. Further, the binding energies of the neutral alanine–benzene complexes were assessed at coupled cluster (CCSD)/6‐31G(d,p) method. Analysis of the molecular geometries and interaction energies at density functional theory (DFT), MP2, CCSD methods and CCSD(T) single point level reveal that MP2 is the best overall performer for noncovalent interactions giving accuracy close to CCSD method. MPWB1K fared better in interaction energy calculations than other DFT methods. In the case of M06‐2X, SVWN5, and the dispersion corrected B97‐D, the interaction energies are significantly overrated for neutral systems compared to other methods. However, for cationic systems, B97‐D yields structures and interaction energies similar to MP2 and MPWB1K methods. Among the long‐range corrected methods, LC‐ωPBE and CAM‐B3LYP methods show close agreement with MP2 values while ωB97XD energies are notably higher than MP2 values.

Molecular electrostatics for probing lone pair–π interactions

An electrostatics-based approach has been proposed for probing the weak interactions between lone pair containing molecules and π deficient molecular systems. For electron-rich molecules, the negative minima in molecular electrostatic potential (MESP) topography give the location of electron localization and the MESP value at the minimum (Vmin) quantifies the electron-rich character of that region. Interactive behavior of a lone pair bearing molecule with electron deficient π-systems, such as hexafluorobenzene, 1,3,5-trinitrobenzene, 2,4,6-trifluoro-1,3,5-triazine and 1,2,4,5-tetracyanobenzene explored within DFT brings out good correlation of the lone pair-π interaction energy (E(int)) with the Vmin value of the electron-rich system. Such interaction is found to be portrayed well with the Electrostatic Potential for Intermolecular Complexation (EPIC) model. On the basis of the precise location of MESP minimum, a prediction for the orientation of a lone pair bearing molecule with an electron deficient π-system is possible in the majority of the cases studied.

A Molecular Electrostatic Potential Analysis of Hydrogen, Halogen, and Dihydrogen Bonds

Hydrogen, halogen, and dihydrogen bonds in weak, medium and strong regimes (<1 to ∼ 60 kcal/mol) have been investigated for several intermolecular donor-acceptor (D-A) complexes at ab initio MP4//MP2 method coupled with atoms-in-molecules and molecular electrostatic potential (MESP) approaches. Electron density ρ at bond critical point correlates well with interaction energy (Enb) for each homogeneous sample of complexes, but its applicability to the entire set of complexes is not satisfactory. Analysis of MESP minimum (V(min)) and MESP at the nuclei (Vn) shows that in all D-A complexes, MESP of A becomes more negative and that of D becomes less negative suggesting donation of electrons from D to A leading to electron donor-acceptor (eDA) interaction between A and D. MESP based parameter ΔΔVn measures donor-acceptor strength of the eDA interactions as it shows a good linear correlation with Enb for all D-A complexes (R(2) = 0.976) except the strongly bound bridged structures. The bridged structures are classified as donor-acceptor-donor complexes. MESP provides a clear evidence for hydrogen, halogen, and dihydrogen bond formation and defines them as eDA interactions in which hydrogen acts as electron acceptor in hydrogen and dihydrogen bonds while halogen acts as electron acceptor in halogen bonds.

Lone Pairs: An Electrostatic Viewpoint

A clear-cut definition of lone pairs has been offered in terms of characteristics of minima in molecular electrostatic potential (MESP). The largest eigenvalue and corresponding eigenvector of the Hessian at the minima are shown to distinguish lone pair regions from the other types of electron localization (such as π bonds). A comparative study of lone pairs as depicted by various other scalar fields such as the Laplacian of electron density and electron localization function is made. Further, an attempt has been made to generalize the definition of lone pairs to the case of cations.

Typical aromatic noncovalent interactions in proteins: A theoretical study using phenylalanine

A systematic study of CH···π, OH···π, NH···π, and cation···π interactions has been done using complexes of phenylalanine in its cationic, anionic, neutral, and zwitterionic forms with CH4, H2O, NH3, and NH  4+ at B3LYP, MP2, MPWB1K, and M06‐2X levels of theory. All noncovalent interactions are identified by the presence of bond critical points (bcps) of electron density (ρ(r)) and the values of ρ(r) showed linear relationship to the binding energies (Etotal). The estimated Etotal from supermolecule, fragmentation, and ρ(r) approaches suggest that cation···π interactions are in the range of 36 to 46 kcal/mol, whereas OH···π, and NH···π interactions have comparable strengths of 6 to 27 kcal/mol and CH···π interactions are the weakest (0.62–2.55 kcal/mol). Among different forms of phenylalanine, cationic form generally showed the highest noncovalent interactions at all levels of theory. Cooperativity of multiple interactions is analyzed on the basis of ρ(r) at bcps which suggests that OH···π and NH···π interactions show positive, whereas CH···π and cation···π interactions exhibit negative cooperativity with respect to the side chain hydrogen bond interactions. In general, side chain interactions are strengthened as a result of aromatic interaction. Solvation has no significant effect on the overall geometry of the complex though slight weakening of noncovalent interactions by 1–2 kcal/mol is observed. An assessment of the four levels of theory studied herein suggests that both MPWB1K and M06‐2X give better performance for noncovalent interactions. The results also support the fact that B3LYP is inadequate for the study of weak interactions.

Role of structural water molecule in HIV protease‐inhibitor complexes: A QM/MM study

Structural water molecule 301 found at the interface of HIV protease‐inhibitor complexes function as a hydrogen bond (H‐bond) donor to carbonyl groups of the inhibitor as well as H‐bond acceptor to amide/amine groups of the flap region of the protease. In this study, six systems of HIV protease‐inhibitor complexes were analyzed, which have the presence of this “conserved” structural water molecule using a two‐layer QM/MM ONIOM method. The combination of QM/MM and QM method enabled the calculation of strain energies of the bound ligands as well as the determination of their binding energies in the ligand–water and ligand–water–protease complexes. Although the ligand experiences considerable strain in the protein bound structure, the H‐bond interactions through the structural water overcomes this strain effect to give a net stability in the range of 16–24 kcal/mol. For instance, in 1HIV system, the strain energy of the ligand was 12.2 kcal/mol, whereas the binding energy associated with the structural water molecule was 20.8 kcal/mol. In most of the cases, the calculated binding energy of structural water molecule showed the same trend as that of the experimental binding free energy values. Further, the classical MD simulations carried out on 1HVL system with and without structural water 301 showed that this conserved water molecule enhances the H‐bond dynamics occurring at the Asp‐bound active site region of the protease‐inhibitor system, and therefore it will have a direct influence on the mechanism of drug action.

Anion Receptors Based on Highly Fluorinated Aromatic Scaffolds

Mono-, di-, and tri-pentafluorobenzyl-substituted hexafluorobenzene (HFB) scaffolds, viz., R(I), R(II), and R(III) are proposed as promising receptors for molecules of chemical, biological, and environmental relevance, viz., N2, O3, H2O, H2O2, F(-), Cl(-), BF4(-), NO3(-), ClO(-), ClO2(-), ClO3(-), ClO4(-), and SO4(2-). The receptor-guest complexes modeled using M06L/6-311++G(d,p) DFT show a remarkable increase in the complexation energy (E(int)) with an increase in the number of fluorinated aromatic moieties in the receptor. Electron density analysis shows that fluorinated aromatic moieties facilitate the formation of large number of lone pair-π interactions around the guest molecule. The lone pair strength of the guest molecules quantified in terms of the absolute minimum (V(min)) of molecular electrostatic potential show that E(int) strongly depends on the electron deficient nature of the receptor as well as strength of lone pairs in the guest molecule. Compared to HFB, R(I) exhibits 1.1-2.5-fold, R(II) shows 1.6-3.6-fold, and the bowl-shaped R(III) gives 1.8-4.7-fold increase in the magnitude of E(int). For instance, in the cases of HFB···F(-), R(I)···F(-), R(II)···F(-), and R(III)···F(-) the E(int) values are -21.1, -33.7, -38.1, and -50.5 kcal/mol, respectively. The results strongly suggest that tuning lone pair-π interaction provides a powerful strategy to design receptors for small molecules and anions.

Mechanism of epoxide hydrolysis in microsolvated nucleotide bases adenine, guanine and cytosine: A DFT study

Six water molecules have been used for microsolvation to outline a hydrogen bonded network around complexes of ethylene epoxide with nucleotide bases adenine (EAw), guanine (EGw) and cytosine (ECw). These models have been developed with the MPWB1K-PCM/6-311++G(3df,2p)//MPWB1K/6-31+G(d,p) level of DFT method and calculated S(N)2 type ring opening of the epoxide due to amino group of the nucleotide bases, viz. the N6 position of adenine, N2 position of guanine and N4 position of cytosine. Activation energy (E(act)) for the ring opening was found to be 28.06, 28.64, and 28.37 kcal mol(-1) respectively for EAw, EGw and ECw. If water molecules were not used, the reactions occurred at considerably high value of E(act), viz. 53.51 kcal mol(-1) for EA, 55.76 kcal mol(-1) for EG and 56.93 kcal mol(-1) for EC. The ring opening led to accumulation of negative charge on the developing alkoxide moiety and the water molecules around the charge localized regions showed strong hydrogen bond interactions to provide stability to the intermediate systems EAw-1, EGw-1 and ECw-1. This led to an easy migration of a proton from an activated water molecule to the alkoxide moiety to generate a hydroxide. Almost simultaneously, a proton transfer chain reaction occurred through the hydrogen bonded network of water molecules and resulted in the rupture of one of the N-H bonds of the quaternized amino group. The highest value of E(act) for the proton transfer step of the reaction was 2.17 kcal mol(-1) for EAw, 2.93 kcal mol(-1) for EGw and 0.02 kcal mol(-1) for ECw. Further, the overall reaction was exothermic by 17.99, 22.49 and 13.18 kcal mol(-1) for EAw, EGw and ECw, respectively, suggesting that the reaction is irreversible. Based on geometric features of the epoxide-nucleotide base complexes and the energetics, the highest reactivity is assigned for adenine followed by cytosine and guanine. Epoxide-mediated damage of DNA is reported in the literature and the present results suggest that hydrated DNA bases become highly S(N)2 active on epoxide systems and the occurrence of such reactions can inflict permanent damage to the DNA.

Aromatization Energy and Strain Energy of Buckminsterfullerene from Homodesmotic Reactions

The amount of aromatic stabilization of C60 fullerene (E(aroma)) and the amount of its destabilizing strain effect (E(strain)) are unknown quantities because both are intimately connected and difficult to separate. Based on experimentally known transformation of C60H30 to C60 and conversion of a polycyclic aromatic hydrocarbon C60H20 to the nonaromatic linear conjugated C60H62, new homodesmotic reaction schemes have been proposed to evaluate E(aroma) and E(strain). The E(aroma) values obtained at M06L/6-311G(d,p), M062X/6-311G(d,p), and B3LYP-D3/6-311G(d,p) levels of density functional theory are 122.3, 169.8, and 152.4 kcal/mol, respectively, whereas E(strain) values at these levels are 327.3, 382.0, and 381.4 kcal/mol, respectively. These data suggest that a CC bond of C60 is destabilized by ∼2.28-2.54 kcal/mol compared to that of benzene, and this minor energetic effect explains the existence of C60 as a stable molecule.

A Noncovalent Binding Strategy to Capture Noble Gases, Hydrogen and Nitrogen: A Noncovalent Binding Strategy

A molecular design strategy to develop receptor systems for the entrapment of noble gases, H2 and N2 is described using M06L‐D3/6‐311++G(d,p)//M06L/6‐311++G(d,p) DFT method. These receptors made with two‐, three‐, four‐ and five‐fluorinated benzene cores, linked with methelene units viz. RI, RII, RIII and RIV as well as the corresponding non‐fluorinated hydrocarbons viz. RIH, RIIH, RIIIH and RIVH show a steady and significant increase in binding energy (Eint) with increase in the number of aromatic rings in the receptor. A stabilizing “cage effect” is observed in the cyclophane type receptors RIV and RIVH which is 26–48% of total Eint for all except the larger sized Kr, Xe and N2 complexes. Eint of RIV…He, RIV…Ne, RIV…Ar, RIV…Kr, RIV…H2 and RIV…N2 is 4.89, 7.03, 6.49, 6.19, 8.57 and 8.17 kcal/mol, respectively which is 5‐ to9‐fold higher than that of hexafluorobenzene. Similarly, compared to benzene, multiple fold increase in Eint is observed for RIVH receptors with noble gases, H2 and N2. Fluorination of the aromatic core has no significant impact on Eint (∼ ±0.5 kcal/mol) for most of the systems with a notable exception of the cage receptor RIV for N2 where fluorination improves Eint by 1.61 kcal/mol. The Eint of the cage receptors may be projected as one of the highest interaction energy ranges reported for noble gases, H2 and N2 for a neutral carbon framework. Synthesis of such systems is promising in the study of molecules in confined environment.