Mechanistic variances in NO release: ortho vs. meta isomers of nitrophenol and nitroaniline.

The NO release following 266 nm photolysis of ortho and meta isomers of nitrophenol and nitroaniline shows a bimodal translational energy distribution, wherein the slow and fast components originate from dynamics in the S0 and T1 states, respectively. The translational energy distribution profiles for any NO product state show a higher slow-to-fast (s/f) branching ratio for the ortho isomer in comparison with the meta isomer. The observed variation in the s/f branching ratio vis-à-vis the ortho and meta isomers is attributed to the presence of intramolecular hydrogen bonding between the ortho substituent and NO2 moiety, which favours the roaming mechanism.

Unraveling the Significance of Mg2+ Dependency and Nucleotide Binding Specificity of H-RAS.

RAS is a small GTPase and acts as a binary molecular switch; the transition from its active to inactive state plays a crucial role in various cell signaling processes. Molecular dynamics simulations at the atomistic level suggest that the absence of cofactor Mg2+ ion generally leads to pronounced structural changes in the Switch-I than Switch-II regions and assists GTP binding. The presence of the Mg2+ ion also restricts the rotation of ϒ phosphate and enhances the hydrolysis rate of GTP. Further, the simulations reveal that the stability of the protein is almost uncompromised when Mg2+ is replaced with Zn2+ and not the Ca2+ ion. The specificity of H-RAS to GTP was evaluated by substituting with ATP and CTP, which indicates that the binding pocket tolerates purine bases over pyrimidine bases. However, the D119 residue specifically interacts with the guanine base and serves as one of the primary interactions that leads to the selectivity of GTP over ATP. The ring displacement of 32Y serves as gate dynamics in H-RAS which are important for its interaction with GAP for the nucleotide exchange and is restricted in the presence of ATP. Finally, the point mutations 61, 16, and 32 influence the structural changes, specifically in the Switch-II region, which are expected to impact the GTP hydrolysis and thus are termed oncogenic mutations.

Dissociative Photoionization of Dimethylpyridines and Trimethylpyridine at 266 nm: Dynamics of Methyl Radical Release.

The 266 nm photolysis of various positional isomers of dimethylpyridines and trimethylpyridine was investigated by measuring the translational energy distribution of the methyl radical following {sp2}C-C{sp3} bond dissociation. The observed translational energy distribution is attributed to the dissociative photoionization in the cationic ground state following [1 + 1 + 1] three-photon absorption. The translational energy distribution profiles of the methyl radical were broad with the maximum translation energy in excess of 2 eV, which originates due to the dissociation of {sp2}C-C{sp3} bond ortho to the N atom in the ring. The dynamics of {sp2}C-C{sp3} bond dissociation in the cationic ground state of methylpyridines is marginally dependent on the number and position of the methyl groups; similar to xylenes, however, it is site-selective with the preferential cleavage of C-C bond in the ortho position to the pyridinic nitrogen atom, which is attributed to the relative stability of the resulting radical cation.

Enticing a Proton using Single Ammonia Molecule as Bait.

In microhydrated acid-solvent clusters, deprotonation of an acid is assisted by a critical number of solvent molecules and a solvent electric field. Born-Oppenheimer molecular dynamics simulations reveal that trifluoroacetic acid undergoes spontaneous proton transfer in water clusters, with the critical number being five. Acetic acid and phenol, on the other hand, do not dissociate even in the presence of a large number of water molecules (in excess of 40). The addition of a single ammonia molecule to the water cluster, which interacts directly with the protic group, lowers the critical number of solvent water molecules required for proton transfer to three and seven in the case of acetic acid and phenol, respectively. The population of the undissociated and the proton-transferred structures get dispersed to form separate islands on the electric field versus the O-H distance representation with the cusp representing the critical values. The critical electric fields for the spontaneous proton transfer are around 254, 237, and 318 MV cm-1 for trifluoroacetic acid, acetic acid, and phenol, respectively. In the case of phenol, the free energy profiles suggest that proton transfer to the ammonia moiety embedded in water promotes proton transfer efficiently due to the higher basicity of ammonia and enhanced hydrogen bonding network of solvent water, vis-à-vis phenol-ammonia clusters.

Ab initio anharmonic analysis of complex vibrational spectra of phenylacetylene and fluorophenylacetylenes in the acetylenic and aromatic C-H stretching region.

Vibrational spectra in the acetylenic and aromatic C-H stretching regions of phenylacetylene and fluorophenylacetylenes, viz., 2-fluorophenylacetylene, 3-fluorophenylacetylene, and 4-fluorophenylacetylene, were measured using the IR-UV double resonance spectroscopic method. The spectra, in both acetylenic and aromatic C-H stretching regions, were complex exhibiting multiple bands. Ab-initio anharmonic calculations with quartic potential using B97D3/6-311++G(d,p) and vibrational configuration interaction were able to capture all important spectral features in both the regions of the experimentally observed spectra for all four molecules considered in the present work. Interestingly, for phenylacetylene, the spectrum in the acetylenic C-H stretching region emerges due to anharmonic coupling of modes localized on the acetylenic moiety along with the other ring modes, which also involve displacements on the acetylenic group, which is in contrast to what has been proposed and propagated in the literature. In general, this coupling scheme is invariant to the fluorine atom substitution. For the aromatic C-H stretching region, the observed spectrum emerges due to the coupling of the C-H stretching with C-C stretching and C-H in-plane bending modes.

Photodegradation of Flutamide and Halogen Derivatives of Nitrobenzotrifluoride: The NO Release Channel.

The photodegradation of the nonsteroidal antiandrogen drug flutamide has been long linked to the photoisomerization involving the nitro group. In this work, the dynamics of NO photoelimination upon photolysis at 266 nm of flutamide, nitrobenzotrifluoride, and its halogen derivatives were investigated. Similar to nitrobenzene and its derivatives, a bimodal translational energy distribution was observed for the NO photofragment indicating the presence of two distinct elimination channels resulting in slow and fast components. The trends in the slow/fast branching ratio show that halogen substitution at the para position increases the triplet state yield due to the internal heavy-atom effect leading to enhancement of the fast component. Furthermore, the topology of the triplet state potential energy surface showed that the minimum energy path favors the oxaziridine ring-type intermediate over the NO2 roaming mechanism in all five molecules investigated. The steric interaction between the NO2 group and the CF3 group, which are placed in the ortho position, lowers the barrier for the formation of the oxaziridine transition state compared to that of nitrobenzene.

Dynamics of Hydrogen Bond Breaking Induced by Outer-Valence Intermolecular Coulombic Decay.

The photoexcitation of weakly bound complexes can lead to several decay pathways, depending on the nature of the potential energy surfaces. Upon excitation of a chromophore in a weakly bound complex, ionization of its neighbor upon energy transfer can occur due to a unique relaxation process known as intermolecular Coulombic decay (ICD), a phenomenon of renewed focus owing to its relevance in biological systems. Herein, we report the evidence for outer-valence ICD induced by multiphoton excitation by near-ultraviolet radiation of 4.4 eV photons, hitherto unknown in molecular systems. In the binary complexes of 2,6-difluorophenylacetylene with aliphatic amines, a resonant two-photon excitation localized on the 2,6-difluorophenylacetylene chromophore results in the formation of an amine cation following an outer-valence ICD process. The unique trends in experimentally observed translational energy distribution profiles of the amine cations following hydrogen bond dissociation, analyzed with the help of electronic structure and ab initio molecular dynamics calculations, revealed the presence of a delicate interplay of roaming dynamics, methyl-rotor dynamics, and binding energy.

Dissociation of Endohedrally Encapsulated HCl/HBr in C60 and C70: An Electric Field Perspective.

The ability of an acid to undergo dissociation depends primarily on the nature of the solvent and especially the arrangement of the solvent molecules around the protic group. This process of acid dissociation can be promoted by confining the solute-solvent system to nanocavities. Endohedral confinement of HCl/HBr complexed with a single ammonia or a water dimer within the C60/C70 cage results in the dissociation of mineral acid. Such confinement bolsters the electric field along the H-X bond and consequently lowers the minimum number of solvent molecules required in the gas phase for the acid dissociation.

Modulating the Roaming Dynamics for the NO Release in ortho-Nitrobenzenes.

The dynamics of NO release upon photodissociation of nitroaromatic compounds is dependent on the nature of the interaction between the NO2 group and substituent in the ortho position. A bimodal (slow and fast) translational energy distribution of the NO photofragment indicates the presence of two distinct NO elimination channels. The slow-to-fast branching ratio for the NO release is regulated by the hydrogen bonding ability of the ortho substituent and follows the order [OH > NH2 > CH3 > OCH3], indicating that the intramolecular hydrogen bonding plays a pivotal role in NO release dynamics. Further, the topology of the triplet state potential energy surface acts as a doorway to the dissociation pathway switching between the roaming and nonroaming mechanisms, with hydrogen bonding substituents (OH and NH2) favoring the roaming mechanism.

Expanding the Horizon of Bio-Inspired Catalyst Design with Tactical Incorporation of Drug Molecules.

The development of potent H2 production catalysts is a key aspect in our journey toward the establishment of a sustainable carbon-neutral power infrastructure. Hydrogenase enzymes provide the blueprint for designing efficient catalysts by the rational combination of central metal core and protein scaffold-based outer coordination sphere (OCS). Traditionally, a biomimetic catalyst is crafted by including natural amino acids as OCS features around a synthetic metal motif to functionally imitate the metalloenzyme activity. Here, we have pursued an unconventional approach and implanted two distinct drug molecules (isoniazid and nicotine hydrazide) at the axial position of a cobalt core to create a new genre of synthetic catalysts. The resultant cobalt complexes are active for both electrocatalytic and photocatalytic H2 production in near-neutral water, where they significantly enhance the catalytic performance of the unfunctionalized parent cobalt complex. The drug molecules showcased a dual effect as they influence the catalytic HER by improving the surrounding proton relay along and exerting subtle electronic effects. The isoniazid-ligated catalyst C1 outperformed the nicotine hydrazide-bound complex C2, as it produced H2 from water (pH 6.0) at a rate of 3960 s-1 while exhibiting Faradaic efficiency of about 90 %. This strategy opens up newer avenues of bio-inspired catalyst design beyond amino acid-based OCS features.

Identification of allosteric hotspots regulating the ribosomal RNA binding by antibiotic resistance-conferring Erm methyltransferases.

Antibiotic resistance via epigenetic methylation of ribosomal RNA is one of the most prevalent strategies adopted by multidrug resistant pathogens. The erythromycin-resistance methyltransferase (Erm) methylates rRNA at the conserved A2058 position and imparts resistance to macrolides such as erythromycin. However, the precise mechanism adopted by Erm methyltransferases for locating the target base within a complicated rRNA scaffold remains unclear. Here, we show that a conserved RNA architecture, including specific bulge sites, present more than 15 Å from the reaction center, is key to methylation at the pathogenic site. Using a set of RNA sequences site-specifically labeled by fluorescent nucleotide surrogates, we show that base flipping is a prerequisite for effective methylation and that distal bases assist in the recognition and flipping at the reaction center. The Erm-RNA complex model revealed that intrinsically flipped-out bases in the RNA serve as a putative anchor point for the Erm. Molecular dynamic simulation studies demonstrated the RNA undergoes a substantial change in conformation to facilitate an effective protein-rRNA handshake. This study highlights the importance of unique architectural features exploited by RNA to impart fidelity to RNA methyltransferases via enabling allosteric crosstalk. Moreover, the distal trigger sites identified here serve as attractive hotspots for the development of combination drug therapy aimed at reversing resistance.

Dynamics of Methyl Radical Formation Following 266 nm Dissociative Photoionization of Xylenes and Mesitylene.

The 266 nm dissociative photoionization of three xylene isomers and mesitylene leading to the formation of methyl radical was examined. The total translational energy distribution profiles [P(ET)] for the methyl radical were almost identical for all of the three isomers of xylene and mesitylene, while a substantial difference was observed for the corresponding P(ET) profile of the co-fragment produced by loss of one methyl group in m-xylene. This observation is attributed to the formation of the methyl radical from alternate channels induced by the probe. The P(ET) profiles were rationalized based on the dissociation of {sp2}C-C{sp3} bond in the cationic state, wherein the {sp2}C-C{sp3} bond dissociation energy is substantially lower relative to the neutral ground state. The dissociation in the cationic state follows a resonant three-photon absorption process, resulting in a maximum translational energy of about 1.6-1.8 eV for the photofragments in the center-of-mass frame. Fitting of the P(ET) profiles to empirical function reveals that the dynamics of {sp2}C-C{sp3} bond dissociation is insensitive to the position of substitution but marginally dependent on the number of methyl groups.

Binary Matrix Method to Enumerate, Hierarchically Order, and Structurally Classify Peptide Aggregation.

Protein aggregation is a common and complex phenomenon in biological processes, yet a robust analysis of this aggregation process remains elusive. The commonly used methods such as center-of-mass to center-of-mass (COM-COM) distance, the radius of gyration (Rg), hydrogen bonding (HB), and solvent accessible surface area do not quantify the aggregation accurately. Herein, a new and robust method that uses an aggregation matrix (AM) approach to investigate peptide aggregation in a MD simulation trajectory is presented. An nxn two-dimensional AM is created by using the interpeptide Cα-Cα cutoff distances, which are binarily encoded (0 or 1). These aggregation matrices are analyzed to enumerate, hierarchically order, and structurally classify the aggregates. Comparison of the present AM method suggests that it is superior to the HB method since it can incorporate nonspecific interactions and the Rg and COM-COM methods since the cutoff distance is independent of the length of the peptide. More importantly, the present method can structurally classify the peptide aggregates, which the conventional Rg, COM-COM, and HB methods fail to do. The unique selling point of this method is its ability to structurally classify peptide aggregates using two-dimensional matrices.

Vibrational Stark fields in carboxylic acid dimers.

Carboxylic acids form exceptionally stable dimers and have been used to model proton and double proton transfer processes. The stabilization energies of the carboxylic acid dimers are very weakly dependent on the nature of substitution. However, the electric field experienced by the OH group of a particular carboxylic acid is dependent more on the nature of the substitution on the dimer partner. In general, the electric field was higher when the partner was substituted with an electron-donating group and lower with an electron-withdrawing substituent on the partner. The Stark tuning rate (Δ) of the O-H stretching vibrations calculated at the MP2/aug-cc-pVDZ level was found to be weakly dependent on the nature of substitution on the carboxylic acid. The average Stark tuning rate of O-H stretching vibrations of a particular carboxylic acid when paired with other acids was 5.7 cm-1 (MV cm-1)-1, while the corresponding average Stark tuning rate of the partner acids due to a particular carboxylic acid was 21.9 cm-1 (MV cm-1)-1. The difference in the Stark tuning rate is attributed to the primary and secondary effects of substitution on the carboxylic acid. The average Stark tuning rate for the anharmonic O-D frequency shifts is about 40-50% higher than the corresponding harmonic O-D frequency shifts calculated at the B3LYP/aug-cc-pVDZ level, much greater than the typical scaling factors used, indicating the strong anharmonicity of O-H/O-D oscillators in carboxylic acid dimers. Finally, the linear correlation observed between pKa and the electric field was used to estimate the pKa of fluoroformic acid to be around 0.9.

Ultrafast Proton-Transfer Reaction in Phenol-(Ammonia)n Clusters: An Ab Initio Molecular Dynamics Investigation.

The ability of phenol to transfer a proton to surrounding ammonia molecules in a phenol-(ammonia)n cluster depends on the relative orientation of ammonia molecules, and a critical field of about 285 MV cm-1 is essential along the O-H bond for the proton-transfer process. Ab initio MD simulations reveal that the proton-transfer process from phenol to ammonia cluster is spontaneous when the cluster has at least eight ammonia molecules, and the proton-transfer event is almost instantaneous (about 20-120 fs). These simulations also reveal that the rate-determining step for the proton-transfer process is the reorganization of the solvent around the OH group. During the solvent reorganization process, the fluctuations in the solvent occur until a particular set of configurations projects the field in excess of the critical electric field along the O-H bond which drives the proton-transfer process. Further, the proton-transfer process follows a curvilinear path which includes the O-H bond elongation and out-of-plane movement of the proton and can be referred to as a "bend-to-break" process.

Is Dissociation of HCl in DMSO Clusters Bistable?

Dissociation of HCl embedded in dimethyl sulfoxide (DMSO) clusters was investigated by projecting the solvent electric field along the HCl bond using B3LYP-D3/6-31+G(d) and MP2/6-31+G(d,p) levels of theory. A large number of distinct structures (about 1500) consisting of up to five DMSO molecules were considered in the present work for statistical reliability. The B3LYP-D3 calculations reveal that the dissociation of HCl embedded in DMSO clusters requires a critical electric field of 138 MV cm-1 along the H-Cl bond. However, a large number of exceptions wherein the electric field values much higher than the critical electric field of 138 MV cm-1 did not result in dissociation of HCl were observed, in addition to several cases wherein the HCl dissociates with an electric field less than the critical electric field. On the other hand, the MP2 level calculations reveal that the critical electric field for HCl dissociation is about 181 MV cm-1 with almost no exceptions. A comparison of calculations carried out using the MP2 and the B3LYP-D3 levels suggests that the dissociation of HCl embedded in DMSO clusters is bistable at the B3LYP-D3 level, which is an artifact, suggesting that care must be exercised in interpreting the processes of proton transfer. The answer to the question raised as the title of this paper is NO.

Π-Stacking in Heterodimers of Propargylbenzene with (Fluoro)phenylacetylenes.

The heterodimers of propargylbenzene (PrBz) with phenylacetylene (PHA) and monosubstituted fluorophenylacetylenes (FPHAs) were investigated using electronic and vibrational spectroscopic methods. The vibrational spectra in the acetylenic C-H stretching region show a marginal shift (0-4 cm-1) upon dimer formation, which suggests minimal perturbation of the acetylenic group. The M06-2X/aug-cc-pVDZ calculations indicate that the π-stacked structures are the most stable, followed by other structures. In general, structures incorporating aromatic C-H···π interactions are much higher in energy. The appearance of the spectra and the energy considerations clearly indicate the preference for the π-stacked structures. Furthermore, the observed trend in the stabilization energies for heterodimers with the three FPHAs is inversely proportional to the dipole moments of FPHAs. On the other hand, the absence of any clear trends in the electrostatic component of the interaction energy is attributed to the presence of the methylene group in PrBz.

Dipole moment enhanced π-π stacking in fluorophenylacetylenes is carried over from gas-phase dimers to crystal structures propagated through liquid like clusters.

The aggregates of monofluorinated phenylacetylenes in the gas-phase, investigated using the IR-UV double resonance spectroscopic method in combination with extensive structural search and electronic structure calculations, reveal the formation of liquid-like clusters with a π-stacked dimeric core. The structural assignment based on the IR spectra in the acetylenic and aromatic C-H stretching regions suggests that, unlike the parent non-fluorinated phenylacetylene, the substitution of a F atom on the phenyl ring increases the dipole moment, leading to robustness in the formation of a ππ stacked dimer, which propagates incorporating C-Hπ_{Ar/Ac} and C-HF interactions involving both acetylenic and aromatic C-H groups. The structural evolution of fluorophenylacetylene aggregates in the gas phase shows marginal effects due to fluorine atom position on the phenyl ring, with substitution in the para-position tending towards phenylacetylene. The present study signifies that the ππ stacked dimers act as a nucleus for the growth of higher clusters to which other molecular units are added predominantly via the {Ar}_C-Hπ_{Ar} type of interaction and the dominant interactions present in the crystal structures gradually emerge with increasing cluster size. Based on these features, gas-phase clusters of fluorophenylacetylene are hypothesized as "liquid-like clusters" acting as intermediates in the generation of various polymorphic forms starting from a ππ stacked dimer as the core molecular unit.

Understanding Fermi resonances in the complex vibrational spectra of the methyl groups in methylamines.

Vibrational spectra of the methyl groups in mono-methylamine (MMA), dimethylamine (DMA), and trimethylamine (TMA) monomers and their clusters were measured in three experimental set-ups to capture their complex spectral features as a result of bend/umbrella-stretch Fermi resonance (FR). Multiple bands were observed between 2800 and 3000 cm-1 corresponding to the methyl groups for MMA and DMA. On the other hand, the corresponding spectrum of TMA is relatively simple, exhibiting only four prominent bands in the same frequency window, even though TMA has a larger number of methyl groups. The discrete variable representation (DVR) based ab initio anharmonic algorithm with potential energy surface (PES) at CCSD/aug-cc-pVDZ quality is able to capture all the experimentally observed spectral features across all three amines, and the constructed vibrational Hamiltonian was used to analyze the couplings that give rise to the observed FR patterns. It was observed that the vibrational coupling among CH stretch modes on different methyl groups is weak (less than 2 cm-1) and stronger vibrational coupling is found to localize within a methyl group. In MMA and DMA, the complex feature between 2850 and 2950 cm-1 is a consequence of closely packed overtone states that gain intensities by mixing with the stretching modes. The simplification of the spectral pattern of TMA can be understood by the red-shift of the symmetric CH3 stretching modes by about 80 cm-1 relative to MMA, which causes the symmetric CH3 stretch to shift outside the FR window.

Vibrational spectroscopic signatures of hydrogen bond induced NH stretch-bend Fermi-resonance in amines: The methylamine clusters and other N-H⋯N hydrogen-bonded complexes.

The appearance of multiple bands in the N-H stretching region of the infrared spectra of the neutral methylamine dimer and trimer is a sign of NH bend-stretch anharmonic coupling. Ab initio anharmonic calculations were carried out in a step-wise manner to reveal the origin of various bands observed in the spectrum of the methylamine dimer. A seven-dimensional potential energy surface involving symmetric and asymmetric stretching and bending vibrations of both the hydrogen bond donor and the acceptor along intermolecular-translational modes was constructed using the discrete variable representation approach. The resulting spectrum of the dimer shows five bands that can be attributed to the symmetric stretching (νsym D), asymmetric stretchin (νasym D), and bending overtone (2νbend D) of the donor moiety. These appear along with the combination band arising out of bending vibrations of the donor and acceptor (νbend D + νbend A) and with the combination of the intermolecular translational mode over the donor bending overtone (νtrans + 2νbend D). The spectrum of the trimer essentially consists of all the features seen in the dimer with marginal changes in band positions. The analysis of the experimental spectra based on the two-state deperturbation model and ab initio anharmonic calculations yield a matrix element of about 40 cm-1 for the N-H bend-stretch Fermi resonance coupling. In general, the IR spectra of the hydrogen-bonded amino group depict three sets of bands that arise due to bend-stretch Fermi resonance coupling.