Can MM‐PBSA calculations predict the specificities of protein kinase inhibitors?

An application of the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) protocol to the prediction of protein kinase inhibitor selectivity is presented. Six different inhibitors are placed in equivalent orientations in each of six different receptors. Fully solvated molecular dynamics is then run for 1 ns on each of the 36 complexes, and the resulting trajectories scored, using the implicit solvent model. The results show some correlation with experimentally-determined specificities; anomalies may be attributed to a variety of causes, including difficulties in quantifying induced fit penalties and variabilities in normal modes calculations. Decomposing interaction energies on a per-residue basis yields more useful insights into the natures of the binding modes and suggests that the real value of such calculations lies in understanding interactions rather than outright prediction.     

Can quantum-mechanical calculations yield reasonable estimates of hydrogen-bonding acceptor strength? The case of hydrogen-bonded complexes of methanol

The thermodynamics and some vibrational properties of hydrogen-bonded complexes of methanol with 23 hydrogen-bond acceptors (HBAs) have been determined in CCl(4) by FTIR spectrometry. The experimental sample contains carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine organic bases and covers an energetic range of 13 kJ mol(-1) in the basicity scale (-ΔG), 22 kJ mol(-1) in the affinity scale (-ΔH), and 400 cm(-1) in the spectroscopic scale (Δν((OH))) (from benzene to trimethylphosphane oxide and amines). The experimental results in CCl(4) are compared to those computed in the gas phase at various levels of theory. Ninety five percent of the variance of the red shift and 89% of the variance of the intensification of the OH stretching upon hydrogen bonding are explained by gas-phase B3LYP/6-31+G(d,p) calculations. However, this level does not satisfactorily explain the thermodynamic properties. Only 68% of the variance of the methanol affinity (-ΔH) is taken into account. MP2/aug-cc-pVTZ//B3LYP/6-31+G(d,p) affinity calculations raise the explanation to 77% for all HBAs and to 93% when three outliers (Me(2)SO, Me(3)PO, and tetrahydrothiophene) are excluded. Discrepancies are analyzed in terms of experimental errors, calculation approximations, and solvation.     

Can Cyclen Bind Alkali Metal Azides? A DFT Study as a Precursor to Synthesis

Can cyclen (1,4,7,10‐tetraazacyclododecane) bind alkali metal azides? This question is addressed by studying the geometric and electronic structures of the alkali metal azide‐cyclen [M(cyclen)N₃] complexes using density functional theory (DFT). The effects of adding a second cyclen ring to form the sandwich alkali metal azide‐cyclen [M(cyclen)₂N₃] complexes are also investigated. N₃^? is found to bind to a M⁺(cyclen) template to give both end‐on and side‐on structures. In the end‐on structures, the terminal nitrogen atom of the azide group (N1) bonds to the metal as well as to a hydrogen atom of the cyclen ring through a hydrogen bond in an end‐on configuration to the cyclen ring. In the side‐on structures, the N₃ unit is bonded (in a side‐on configuration to the cyclen ring) to the metal through the terminal nitrogen atom of the azide group (N1), and through the other terminal nitrogen atom (N3) of the azide group by a hydrogen bond to a hydrogen atom of the cyclen ring. For all the alkali metals, the N₃‐side‐on structure is lowest in energy. Addition of a second cyclen unit to [M(cyclen)N₃] to form the sandwich compounds [M(cyclen)₂N₃] causes the bond strength between the metal and the N₃ unit to decrease. It is hoped that this computational study will be a precursor to the synthesis and experimental study of these new macrocyclic compounds; structural parameters and infrared spectra were computed, which will assist future experimental work.     

Does the choice of the crystal structure influence the results of the periodic DFT calculations? A case of glycine alpha polymorph GIPAW NMR parameters computations

Glycine is a common amino acid with relatively complex chemistry in solid state. Although several polymorphs (α, β, δ, γ, ε) of crystalline glycine are known, for NMR spectroscopy the most important is a polymorph, which is used as a standard for calibration of spectrometer performance and therefore it is intensively studied by both experimental methods and theoretical computation. The great scientific interest in a glycine results in a large number of crystallographic information files (CIFs) deposited in Cambridge Structural Database (CSD). The aim of this study was to evaluate the influence of the chosen crystal structure of α glycine obtained in different crystallographic experimental conditions (temperature, pressure and source of radiation of α glycine) on the results of periodic DFT calculation. For this purpose the total of 136 GIPAW calculations of α glycine NMR parameters were performed, preceded by the four approaches (“SP”, “only H”, “full”, “full+cell”) of structure preparation. The analysis of the results of those computations performed on the representative group of 34 structures obtained at various experimental conditions revealed that though the structures were generally characterized by good accuracy (R < 0.05 for most of them) the results of the periodic DFT calculations performed using the unoptimized structures differed significantly. The values of the standard deviations of the studied NMR parameters were in most cases decreasing with the number of optimized parameters. The most accurate results (of the calculations) were in most cases obtained using the structures with solely hydrogen atoms positions optimized. © 2018 Wiley Periodicals, Inc.     

The importance of conformational search: a test case on the catalytic cycle of the Suzuki�CMiyaura cross-coupling

Conformational diversity is an often neglected aspect in computational studies of transition metal complexes, even when relatively large systems are involved. The importance of conformational searches is illustrated through the analysis of the errors that could be caused by a wrong choice of conformers in the computational study of the Suzuki?CMiyaura cross-coupling between CH₂=CHBr and CH₂=CHB(OH)₂ catalyzed by [(PPh₃)₂Pd] or [(P(i-Pr)₃)₂Pd]. The error bars associated with conformational diversity of the [(PPh₃)₂Pd] catalyst range between 0.3 and 6.7?kcal/mol, the values growing up to 11.4?kcal/mol when the more flexible [(P(i-Pr)₃)₂Pd] catalyst is considered.     

Can a Six‐Letter Alphabet Increase the Likelihood of Photochemical Assault to the Genetic Code?

In 2014, two unnatural nucleosides, d5SICS and dNaM, were shown to selectively base pair and replicate with high fidelity in a modified strain of E. coli, thus effectively expanding its genetic alphabet from four to six letters. More recently, a significant reduction in cell proliferation was reported in cells cultured with d5SICS, and putatively with dNaM, upon exposure to brief periods of near‐visible radiation. The photosensitizing properties of the lowest‐energy excited triplet state of both d5SICS and dNaM were implicated in their cytotoxicity. Importantly, however, the excited‐state mechanisms by which near‐visible excitation populates the triplet states of d5SICS and dNaM are currently unknown. In this study, steady‐state and time‐resolved spectroscopies are combined with quantum‐chemical calculations in order to reveal the excited‐state relaxation mechanisms leading to efficient population of the triplet states in these unnatural nucleosides in solution. It is shown that excitation of d5SICS or dNaM with near‐visible light leads overwhelmingly to ultrafast population of their triplet states on the femtosecond time scale. The results presented in this work lend strong support to the proposal that photoexcitation of these unnatural nucleosides can accelerate oxidatively generated damage to DNA and other biomolecules within the cellular environment.     

What are the spectroscopic properties of HFC‐32? Answers from DFT

Although coupled cluster theory coupled to large basis sets can reach impressive accuracies for thermochemical and spectroscopic properties, it is still limited to small/medium sized molecules. Density functional theory (DFT) represents the working option for systems composed of hundreds to thousands heavy atoms. In this context, investigations are required aimed at characterizing the performances of the different density functionals (DF). This work focuses on the study of DFT performances in the prediction of spectroscopic properties, with particular attention to the vibrational problem, by focusing on the CH₂F₂ molecule as a test case. An extensive and systematic investigation is performed on several DFT model chemistries by testing their predictions of molecular constants and vibrational frequencies and intensities against CCSD(T)/aug‐cc‐pCVQZ data. B3LYP, B3PW91, B97‐1, PBE0, TPSSh, M05, M05‐2X, and B2PLYP DFs are used in conjunction with a variety of basis sets. Anharmonic frequencies are derived from the VPT2 treatment of anharmonic‐ and hybrid CCSD(T)/DFT‐force fields. A software for VPT2 computations is also presented. © 2014 Wiley Periodicals, Inc.     

DFT calculations of the electric field gradient at the tin nucleus as a support of structural interpretation by 119Sn Mössbauer spectroscopy

DFT calculations, using an all-electron basis set and with full geometry optimization, were performed on 34 Sn(II) and Sn(IV) compounds of known structure and (119)Sn M?ssbauer parameters, to obtain the theoretical values of the electric field gradient components, V(xx), V(yy), and V(zz), at the tin nucleus. These were used to determine the quantity V = V(zz)[1+ 1/3((V(xx) - V(yy))/((V(zz))(2)](1/2), for each investigated compound, which is related to the quadrupole splitting (DeltaE) parameter according to DeltaE = 1/2eQV, where e is the electronic charge and Q is the quadrupole moment of the tin nucleus. The linear fitting of the correlation plot of the experimental DeltaE, versus the corresponding calculated V values, produced a slope that is equal to 0.93 +/- 0.03 and a correlation coefficient R = 0.982. The value of Q obtained, 15.2 +/- 4.4 fm(2), is in agreement with that previously experimentally determined or calculated by analogous procedures. The calculation method is able to establish the sign of the electric field gradient component V(zz), in agreement with the sign of DeltaE determined experimentally by M?ssbauer-Zeeman spectroscopy. The calculated structural parameters are in good agreement with the corresponding experimental data, determined by X-ray crystallography in the solid state, with average structural deviations of about 3 % for bond lengths and angles in the tin environment. Calculated values of DeltaE were obtained from the calibration fitting constant and from the values of V. By comparing experimental and calculated DeltaE parameters, the structure assignment of configurational isomers was successful in two test cases, in agreement with the experimental X-ray crystallographic structures. These results indicate that the method can be used as a tool to support the routine structure interpretation of tin compounds by (119)Sn M?ssbauer spectroscopy.     

Application of D‐chiro‐Inositol as a Chiral Template for the Diels?Alder Reaction

The Diels? Alder reaction can reliably provide the expected endo‐product in the presence of secondary orbital overlap. It can be considerably more difficult to access a single enantiomer of the exo‐product. In this paper, a D ‐chiro‐inositol derivative is used as a chiral tether to facilitate the regio‐, diastereo‐, and enatioselective cycloaddition between cinnamic acid and hexa‐3,5‐dienoic acid. The Diels? Alder reaction between these two substrates, or their respective esters, does not occur under thermal conditions. Because of the ease of removal of the chiral tether from the resulting cyclohexene, this approach could provide a viable technique to access otherwise unavailable systems.     

How Can Theory Predict the Selectivity of Palladium‐Catalyzed Cross‐Coupling of Pristine Aromatic Molecules?

The new approach for palladium‐catalyzed cross‐coupling of two non‐activated aromatic compounds (D. R. Stuart, K. Fagnou, Science 2007 , 316, 1172) was studied theoretically. The energetic span model (S. Kozuch, S. Shaik, Acc. Chem. Res. 2011 , 44, 101, and references therein) was employed to analyze the kinetic behavior of the catalytic cycle. The computed energy profile, combined with the energetic span model, accounts for the experimental selectivity, which favors the hetero‐coupling of benzene with indole. This selectivity is driven by a fine balance of the entropic contributions and the high ratio of concentrations used for benzene over indole. This analysis may allow future theoretical predictions of how different aromatic compounds can be effectively coupled.     

How Can a Hydrophobic MOF be Water‐Unstable? Insight into the Hydration Mechanism of IRMOFs

We report an ab initio molecular dynamics study of the hydration process in a model IRMOF material. At low water content (one molecule per unit cell), water physisorption is observed on the zinc cation but the free?bound equilibrium strongly favors the free state. This is consistent with the hydrophobic nature of the host matrix and its type‐V isotherm observed in a classical Monte Carlo simulation. At higher loading, a water cluster can be formed at the Zn₄O site and this is shown to stabilize the water‐bound state. This structure rapidly transforms into a linker‐displaced state, where water has fully displaced one arm of a linker and which corresponds to the loss of the material’s fully ordered structure. Thus an overall hydrophobic MOF material can also become water unstable, a feature that has not been fully understood until now.     

Microreactors as Tools for Synthetic Chemists—The Chemists' Round‐Bottomed Flask of the 21st Century?

Will microreactors replace the round‐bottomed flask to perform chemical reactions in the near future? Recent developments in the construction of microstructured reaction devices and their wide‐ranging applications in many different areas of chemistry suggest that they can have a significant impact on the way chemists conduct their experiments. Miniaturizing reactions offers many advantages for the synthetic organic chemist: high‐throughput scanning of reaction conditions, precise control of reaction variables, the use of small quantities of reagents, increased safety parameters, and ready scale‐up of synthetic procedures. A wide range of single‐ and multiphase reactions have now been performed in microfluidic‐based devices. Certainly, microreactors cannot be applied to all chemistries yet and microfluidic systems also have disadvantages. Limited reaction‐time range, high sensitivity to precipitating products, and new physical, chemical, and analytical challenges have to be overcome. This concept article presents an overview of microfluidic devices available for chemical synthesis and evaluates the potential of microreactor technology in organic synthesis.     

How to identify promising metal scavengers? d‐penicillamine with copper as a study case

Therapeutic chelating agents are used to prevent the effects of the metal accumulation. These are molecules that form complexes with transition metals and they are referred here as metal scavengers. The main idea of this investigation is to recognize the most relevant chemical features to identify potential metal scavengers. d ‐penicillamine with copper (DPEN‐Cu) is used for this purpose. The first requirement that must be fulfilled by a good metal scavenger is the exergonicity of the chelating reaction. In the DPEN‐Cu case the most likely complexation pathway was found to have ΔG equal to −24.3 kcal/mol. It is desirable that the chelating molecule could also be a free radical scavenger. d ‐penicillamine is a good free radical scavenger following the hydrogen atom transfer reaction. An additional advantage is that the DPEN‐Cu may act as •OH‐inactivating ligand. It is proposed that chelating agents fulfilling these requirements may be a promising candidate to be used in metal chelation therapies as metal scavengers.     

Can we understand the different coordinations and structures of closed‐shell metal cation‐water clusters?

We present a model potential for studying M(q+)(H(2)O)(n=1,9) clusters where M stands for either Na(+), Cs(+), Ca(2+), Ba(2+), or La(3+). The potential energy surfaces (PES) are explored by the Monte Carlo growth method. The results for the most significant equilibrium structures of the PES as well as for energetics are favorably compared to the best ab initio calculations found in the literature and to experimental results. Most of these complexes have a different coordination number in cluster compared to experimental results in solution or solid phase. An interpretation of the coordination number in clusters is given. In order to well describe the transition between the first hydration sphere and the second one we show that an autocoherent treatment of the electric field is necessary to correctly deal with polarization effects. We also explore the influence of the cation properties (charge, size, and polarizability) on both structures and coordination number in clusters, as well as the meaning of the second hydration sphere. Such an approach shows that the leading term in the interaction energy for a molecule in the second hydration sphere is an electrostatic attraction to the cation and not a hydrogen bond with the water molecules in the first hydration sphere.     

Can a single oxidant with two spin states masquerade as two different oxidants? A study of the sulfoxidation mechanism by cytochrome p450

Density functional calculations were performed on the sulfoxidation reaction by a model compound I (Cpd I) of cytochrome P450. By contrast to previous alkane hydroxylation studies, which exhibit a dominant low-spin (LS) pathway, the sulfoxidation follows a dominant high-spin (HS) reaction. Thus, competing hydroxylation and sulfoxidation processes as observed for instance by Jones et al. (Volz, T. J.; Rock, D. A.; Jones, J. P. J. Am. Chem. Soc. 2002, 124, 9724) are the result of a two-state reactivity scenario, whereby the hydroxylation originates from the LS pathway and the sulfoxidation from the HS pathway. In this manner, two spin states of a single oxidant (Cpd I) can be disguised as two different oxidants. The calculations rule out the possibility that a second oxidant (the ferric peroxide, Cpd 0 species) interferes in the observed results of Jones et al.