Noncovalent Modulation of Chemoselectivity in the Gas Phase Leads to a Switchover in Reaction Type from Heterolytic to Homolytic to Electrocyclic Cleavage.

In the gas phase, thermal activation of supramolecular assemblies such as host-guest complexes leads commonly to noncovalent dissociation into the individual components. Chemical reactions, for example of encapsulated guest molecules, are only found in exceptional cases. As observed by mass spectrometry, when 1-amino-methyl-2,3-diazabicyclo[2.2.2]oct-2-ene (DBOA) is complexed by the macrocycle ß-cyclodextrin, its protonated complex undergoes collision-induced dissociation into its components, the conventional reaction pathway. Inside the macrocyclic cavity of cucurbit[7]uril (CB7), a competitive chemical reaction of monoprotonated DBOA takes place upon thermal activation, namely a stepwise homolytic covalent bond cleavage with the elimination of N2 , while the doubly protonated CB7⋅DBOA complex undergoes an inner-phase elimination of ethylene, a concerted, electrocyclic ring-opening reaction. These chemical reaction pathways stand in contrast to the gas-phase chemistry of uncomplexed monoprotonated DBOA, for which an elimination of NH3 predominates upon collision-induced activation, as a heterolytic bond cleavage reaction. The combined results, which can be rationalized in terms of organic-chemical reaction mechanisms and density-function theoretical calculations, demonstrate that chemical reactions in the gas phase can be steered chemoselectively through noncovalent interactions.

Electrostatic Potential Topology for Probing Molecular Structure, Bonding and Reactivity.

Following the pioneering investigations of Bader on the topology of molecular electron density, the topology analysis of its sister field viz. molecular electrostatic potential (MESP) was taken up by the authors' groups. Through these studies, MESP topology emerged as a powerful tool for exploring molecular bonding and reactivity patterns. The MESP topology features are mapped in terms of its critical points (CPs), such as bond critical points (BCPs), while the minima identify electron-rich locations, such as lone pairs and π-bonds. The gradient paths of MESP vividly bring out the atoms-in-molecule picture of neutral molecules and anions. The MESP-based characterization of a molecule in terms of electron-rich and -deficient regions provides a robust prediction about its interaction with other molecules. This leads to a clear picture of molecular aggregation, hydrogen bonding, lone pair-π interactions, π-conjugation, aromaticity and reaction mechanisms. This review summarizes the contributions of the authors' groups over the last three decades and those of the other active groups towards understanding chemical bonding, molecular recognition, and reactivity through topology analysis of MESP.

Ultrahigh binding affinity of a hydrocarbon guest inside cucurbit[7]uril enhanced by strong host-guest charge matching.

Cucurbit[7]uril (CB[7]) is an artificial macrocyclic molecule that can form exceptionally strong host-guest complexes with binding constants higher than that of the biotin-avidin complex. Despite notable experimental efforts, there do not exist large-scale computational investigations on finding strongly binding guests of CB[7]. Herein, we develop a computational approach based on large-scale molecular modelling to predict strongly binding hydrocarbon motifs. Our results indicate that an expanded cubane (PubChem ID 101402794) will be the most strongly binding hydrocarbon guest of CB[7] among the hundreds of thousands of hydrocarbons in the PubChem database, achieving a binding affinity significantly stronger than those reported in preceding experimental studies. Our findings highlight the important role of charge complementarity in the form of quadrupole electrostatic interactions in enabling the ultrahigh binding affinity of nonpolar guest molecules with CB[7], in addition to other known contributions such as van der Waals interactions and high-energy water release.

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

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. © 2018 Wiley Periodicals, Inc.

A DFT analysis of the ground and charge-transfer excited states of Sc3N@Ih-C80 fullerene coupled with metal-free and zinc-phthalocyanine.

Endohedral metallofullerenes and phthalocyanine derivatives are recognized as excellent active materials in organic photovoltaics (OPVs). The tri-metallic nitride endohedral C80 fullerenes have greater absorption coefficients in the visible region and electron-accepting abilities similar to C60, which can allow for higher efficiencies in OPV devices. In this work, we have investigated the ground and charge transfer excited states of two co-facial donor-acceptor (D-A) molecular conjugates formed by the non-covalent coupling of trimetallic nitride endohedral fullerene (Sc3N@Ih-C80) with metal-free (H2Pc) and zinc-phthalocyanine (ZnPc) chromophores using DFT calculations. The charge transfer (CT) excitation energies are calculated using the perturbative delta-SCF method that enforces orthogonality between the ground and excited states. The binding energies calculated using the PBE and DFT-D3 methods indicate that the dispersion effects play an important role in the stabilization of these complexes. The ground state dipole moment of the Sc3N@C80-H2Pc dyad is much larger than that of Sc3N@C80-ZnPc, but this is reversed in the excited state where the dipole moment of Sc3N@C80-ZnPc increases significantly. The lowest few excitation energies in the gas phase for the two complexes are very close, in the range of 1.51-2.66 eV for Sc3N@C80-ZnPc and 1.51-2.71 eV for the Sc3N@C80-H2Pc complex. However, the lower ionization potential and lower exciton binding energy make the Sc3N@C80-ZnPc dyad a better candidate for OPVs as compared to the Sc3N@C80-H2Pc dyad.

mDCC_tools: characterizing multi-modal atomic motions in molecular dynamics trajectories.

UNLABELLED: We previously reported the multi-modal Dynamic Cross Correlation (mDCC) method for analyzing molecular dynamics trajectories. This method quantifies the correlation coefficients of atomic motions with complex multi-modal behaviors by using a Bayesian-based pattern recognition technique that can effectively capture transiently formed, unstable interactions. Here, we present an open source toolkit for performing the mDCC analysis, including pattern recognitions, complex network analyses and visualizations. We include a tutorial document that thoroughly explains how to apply this toolkit for an analysis, using the example trajectory of the 100 ns simulation of an engineered endothelin-1 peptide dimer. AVAILABILITY AND IMPLEMENTATION: The source code is available for free at http://www.protein.osaka-u.ac.jp/rcsfp/pi/mdcctools/, implemented in C ++ and Python, and supported on Linux. CONTACT: kota.kasahara@protein.osaka-u.ac.jp SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

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 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.

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.

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.

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.

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.

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.

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

A systematic study of CH...pi, OH...pi, NH...pi, and cation...pi interactions has been done using complexes of phenylalanine in its cationic, anionic, neutral, and zwitterionic forms with CH(4), H(2)O, NH(3), 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 (rho(r)) and the values of rho(r) showed linear relationship to the binding energies (E(total)). The estimated E(total) from supermolecule, fragmentation, and rho(r) approaches suggest that cation...pi interactions are in the range of 36 to 46 kcal/mol, whereas OH...pi, and NH...pi interactions have comparable strengths of 6 to 27 kcal/mol and CH...pi 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 rho(r) at bcps which suggests that OH...pi and NH...pi interactions show positive, whereas CH...pi and cation...pi 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.