Total Structure, Electronic Structure and Catalytic Hydrogenation Activity of Metal-Deficient Chiral Polyhydride Cu57 Nanoclusters.

Accurate identifying and in-depth understanding of the defect sites in a working nanomaterial could hinge on establishing specific defect-activity relationships. Yet, atomically precise coinage-metal nanoclusters (NCs) possessing surface vacancy defects are scarce primarily owing to challenges in the synthesis and isolation of such defective NCs. Herein we report a mixed-ligand strategy to synthesizing an intrinsically chiral and metal-deficient copper hydride-rich NC [Cu57 H20 (PET)36 (TPP)4 ]+ (Cu57 H20 ). Its total structure (including hydrides) and electronic structure are well established by combined experimental and computational results. Crystal structure reveals Cu57 H20 features a cube-like Cu8 kernel embedded in a corner-missing metal-ligand shell of Cu49 (PET)36 (TPP)4 . Single Cu vacancy defect site occurs at one corner of the shell, evocative of mono-lacunary polyoxometalates. Theoretical calculations demonstrate that the above-mentioned point vacancy causes one surface hydride exposed as an interfacial capping µ3 -H- , which is accessible in chemical reaction, as proved by deuterated experiment. Moreover, Cu57 H20 shows catalytic activity in the hydrogenation of nitroarene. The success of this work opens the way for the research on well-defined chiral metal-deficient Cu and other metal NCs, including exploring their application in asymmetrical catalysis.

Molecular Simulations of Conformational Transitions within the Insulin Receptor Kinase Reveal Consensus Features in a Multistep Activation Pathway.

Modulating the transitions between active and inactive conformations of protein kinases is the primary means of regulating their catalytic activity, achieved by phosphorylation of the activation loop (A-loop). To elucidate the mechanism of this conformational activation, we applied the string method to determine the conformational transition path of insulin receptor kinase between the active and inactive conformations and the corresponding free-energy profiles with and without A-loop phosphorylation. The conformational change was found to proceed in three sequential steps: first, the flipping of the DFG motif of the active site; second, rotation of the A-loop; finally, the inward movement of the αC helix. The main energetic bottleneck corresponds to the conformational change in the A-loop, while changes in the DFG motif and αC helix occur before and after A-loop conformational change, respectively. In accordance with this, two intermediate states are identified, the first state just after the DFG flipping and the second state after the A-loop rotation. These intermediates exhibit structural features characteristic of the corresponding inactive and active conformations of other protein kinases. To understand the impact of A-loop phosphorylation on kinase conformation, the free energies of A-loop phosphorylation were determined at several states along the conformational transition path using the free-energy perturbation simulations. The calculated free energies reveal that while the unphosphorylated kinase interconverts between the inactive and active conformations, A-loop phosphorylation restricts access to the inactive conformation, thereby increasing the active conformation population. Overall, this study suggests a consensus mechanism of conformational activation between different protein kinases.

Multi-layer 3D Chirality and Double-Helical Assembly in a Copper Nanocluster with a Triple-Helical Cu15 Core.

Conceptually mimicking biomolecules' ability to construct multiple-helical aggregates with emergent properties and functions remains a long-standing challenge. Here we report an atom-precise 18-copper nanocluster (NC), Cu18 H(PET)14 (TPP)6 (NCS)3 (Cu18 H) which contains a pseudo D3 -symmetrical triple-helical Cu15 core. Structurally, Cu18 H may be also viewed as sandwich type of sulfur-bridged chiral copper cluster units [Cu6 -Cu6 -Cu6 ], endowing three-layered 3D chirality. More importantly, the chiral NCs are aggregated into an infinite double-stranded helix supported by intra-strand homonuclear C-H⋅⋅⋅H-C dihydrogen contacts and inter-strand C-H/π and C-H/S interactions. The unique multi-layered 3D chirality and the double-helical assembly of Cu18 H are evocative of DNA. Moreover, the collective behaviours of the aggregated NCs not only exhibit crystallization-induced emission enhancement (CIEE) and aggregation-induced emission enhancement (AIEE) effects in the deep-red region, but also efficiently catalyze electron transfer (ET) reaction. This study thus presents that hierarchical assemblies of atomically defined copper NCs could be intricate as observed for important biomolecules like DNA with emergent properties arising from aggregated behaviours.

LModeA-nano: A PyMOL Plugin for Calculating Bond Strength in Solids, Surfaces, and Molecules via Local Vibrational Mode Analysis.

The analysis of chemical bonding in crystal structures and surfaces is an important research topic in theoretical chemistry. In this work, we present a PyMOL plugin, named LModeA-nano, as implementation of the local vibrational mode theory for periodic systems (Tao et al. J. Chem. Theory Comput. 2019, 15, 1761) assessing bond strength in terms of local stretching force constants in extended systems of one, two, and three dimensions. LModeA-nano can also analyze chemical bonds in isolated molecular systems thus enabling a head-to-head comparison of bond strength across systems with different dimensions in periodicity (0-3D). The new code is interfaced to the output generated by various solid-state modeling packages including VASP, CP2K, Quantum ESPRESSO, CASTEP, and CRYSTAL. LModeA-nano is cross-platform, open-source and freely available on GitHub: https://github.com/smutao/LModeA-nano.

Unusual Intramolecular Motion of ReH92- in K2ReH9 Crystal: Circle Dance and Three-Arm Turnstile Mechanisms Revealed by Computational Studies.

The nonahydridorhenate dianion ReH92- is a unique rhenium polyhydride complex due to its remarkably high coordination number; however, its detailed polytopal rearrangement process in either solution or crystal is so far unclear. In this work, our quantum chemical calculations have identified two previously unreported fluxional mechanisms for the ReH92- dianion in the K2ReH9 crystal: three-arm turnstile rotation and circle dance mechanism. These two polytopal rearrangements in the crystal offer an alternative interpretation to the pulse and wide-line NMR spectra (Farrar et al. J. Chem. Phys. 1969, 51, 3595). The previously postulated hindered rotation of the whole ReH92- dianion in K2ReH9 (White et al. J. Chem. Soc., Faraday Trans. 2 1972, 68, 1414) turns out to be a combination of the above-mentioned two elementary fluxional processes. In addition, our calculations have confirmed the Muetterties' D3h⇌C4v rearrangement as the intramolecular motion for the ReH92- dianion in solution.

Pivotal role of water molecules in the photodegradation of pymetrozine: New insights for developing green pesticides.

Photodegradation of the insecticide pymetrozine (PYM) was studied on surface of wax films, and in aqueous and nonaqueous phase. The half-life of PYM on the wax surface was approximately 250 times longer than in water. Scavenging experiments, laser flash photolysis, and spectra analysis indicated the first singlet excited state of PYM (S1 *PYM) to be the most important photoinduced species initiating the photodegradation. Quantum chemistry calculations identified significant molecular torsion and changes in the structure C-CN-N of S1 *PYM, and the absolute charges of the CN atoms increased and the bond strength weakened. Free energy surface analysis, and O18 labeling experiments further confirmed that the mechanism was two-step photoinduced hydrolysis. The first step is the hydrolysis of S1 *PYM at CN upon reaction with 2-3 water molecules (one H2O molecule as the catalyst). The second step is an intramolecular hydrogen transfer coupled with the cleavage of C-N bond and formation of two cyclic products. During the interactions, water molecules experience catalytic activation by transferring protons, while there is a negligible solvent effect. Clarifying the detailed photodegradation mechanisms of PYM is beneficial for the development of green pesticides that are photostable and effective on leaf surfaces, and photolabile and detoxified in the aquatic environment.

Capturing Individual Hydrogen Bond Strengths in Ices via Periodic Local Vibrational Mode Theory: Beyond the Lattice Energy Picture.

Local stretching force constants derived from periodic local vibrational modes at the vdW-DF2 density functional level have been employed to quantify the intrinsic hydrogen bond strength of 16 ice polymorphs, ices Ih, II, III, IV, V, VI, VII, VIII, IX, XI, XII, XIII, XIV, XV, XVII, and XIX, that are stable under ambient to elevated pressures. Based on this characterization on 1820 hydrogen bonds, relationships between local stretching force constants and structural parameters such as hydrogen bond length and angle were identified. Moreover, different bond strength distributions, from uniform to inhomogeneous, were observed for the 16 ices and could be explained in relation to different local structural elements within ices, that is, rings, that consist of different hydrogen bond types. In addition, criteria for the classification of hydrogen bonds as strong, intermediate, and weak were introduced. The latter was used to explore a different dimension of the water-ice phase diagram. These findings will provide important guidelines for assessing the credibility of new ice structures.

Observation of a bcc-like framework in polyhydrido copper nanoclusters.

Cu is well-known to adopt a face-centered cubic (fcc) structure in the bulk phase. Ligand-stabilized Cu nanoclusters (NCs) with atomically precise structures are an emerging class of nanomaterials. However, it remains a great challenge to have non-fcc structured Cu NCs. In this contribution, we report the syntheses and total structure determination of six 28-nuclearity polyhydrido Cu NCs: [Cu28H16(dppp)4(RS)4(CF3CO2)8] (dppp = 1,3-bis(diphenylphosphino)propane, RSH = cyclohexylthiol, 1; tert-butylthiol, 3; and 2-thiophenethiol, 4) and [Cu28H16(dppe)4(RS)4(CH3CO2)6Cl2] (dppe = 1,2-bis(diphenylphosphino)ethane, RSH = (4-isopropyl)thiophenol, 2; 4-tert-butylbenzenethiol, 5; and 4-tert-butylbenzylmercaptan, 6). Their well-defined structures solved by X-ray single crystal diffraction reveal that these 28-Cu NCs are isostructural, and the overall metal framework is arranged as a sandwich structure with a core-shell Cu2@Cu16 unit held by two Cu5 fragments. One significant finding is that the organization of 18 Cu atoms in the Cu2@Cu16 could be regarded as an incomplete and distorted version of 3 × 2 × 2 "cutout" of the body-centered cubic (bcc) bulk phase, which was strikingly different to the fcc structure of bulk Cu. The bcc framework came as a surprise, as no bcc structures have been previously observed in Cu NCs. A comparison with the ideal bcc arrangement of 18 Cu atoms in the bcc lattice suggests that the distortion of the bcc structure results from the insertion of interstitial hydrides. The existence, number, and location of hydrides in these polyhydrido Cu NCs are established by combined experimental and DFT results. These results have significant implications for the development of high-nuclearity Cu hydride NCs with a non-fcc architecture.

On the formation of CN bonds in Titan's atmosphere-a unified reaction valley approach study.

In this work, we investigated the formation of protonated hydrogen cyanide HCNH+ and methylene amine cation CH[Formula: see text] (both identified in Titan's upper atmosphere) from three different pathways which stem from the interaction between CH4 and N+(3P). As a mechanistic tool, we used the Unified Reaction Valley Approach (URVA) complemented with the Local Mode Analysis (LMA) assessing the strength of the CN bonds formed in these reactions. Our URVA studies could provide a comprehensive overview on bond formation/cleavage processes relevant to the specific mechanism of eight reactions R1- R8 that occur across the three pathways. In addition, we could explain the formation of CH[Formula: see text] and the appearance of HCNH+ and CHNH[Formula: see text] along these paths. Although only smaller molecules are involved in these reactions including isomerization, hydrogen atom abstraction, and hydrogen molecule capture, we found a number of interesting features, such as roaming in reaction R3 or the primary interaction of H2 with the carbon atom in HCNH+ in reaction R8 followed by migration of one of the H2 hydrogen atoms to the nitrogen which is more cost effective than breaking the HH bond first; a feature often found in catalysis. In all cases, charge transfer between carbon and nitrogen could be identified as a driving force for the CN bond formation. As revealed by LMA, the CN bonds formed in reactions R1-R8 cover a broad bond strength range from very weak to very strong, with the CN bond in protonated hydrogen cyanide HCNH+ identified as the strongest of all molecules investigated in this work. Our study demonstrates the large potential of both URVA and LMA to shed new light into these extraterrestrial reactions to help better understand prebiotic processes as well as develop guidelines for future investigations involving areas of complex interstellar chemistry. In particular, the formation of CN bonds as a precursor to the extraterrestrial formation of amino acids will be the focus of future investigations. Formation of CN bonds in Titan's atmosphere visualized via the reaction path curvature.

Systematic Detection and Characterization of Hydrogen Bonding in Proteins via Local Vibrational Modes.

We introduce a new software, Efficient Detection of Hydrogen Bonds (EDHB), that systematically detects hydrogen bonds based on the nearest neighbors algorithm. EDHB classifies inter- and intramolecular hydrogen bonds as well as hydrogen bond networks. EDHB outperforms commonly used hydrogen bond detection methods in terms of speed of execution. An important additional feature of EDHB is that information from preceding quantum chemical studies (i.e., natural bond orbital analysis data and second energy derivative information) can be used to determine the electrostatic/covalent character of the hydrogen bonds and to calculate local-mode hydrogen bond force constants as a quantitative measure of their intrinsic strength. We applied EDHB to a diverse set of 163 proteins. We identified hydrogen bond networks forming intramolecular rings of different sizes as a common feature playing an important role for specific secondary structure orientations such as α-helixes and turns. However, these networks do not have a significant influence on the hydrogen bond strength. Our comprehensive local-mode analysis reveals the interesting result that the hydrogen bond angle is the governing factor determining the hydrogen bond strength in a protein. EDHB offers a broad range of application possibilities. In addition to proteins, EDHB can be generally used to detect and characterize hydrogen bonds in protein-ligand interactions, water clusters, and other systems where a hydrogen bond plays a critical role, as well as during molecular dynamics simulations. The program is freely available at https://github.com/ekraka/EDHB.

A revised formulation of the generalized subsystem vibrational analysis (GSVA).

In this work, a simplified formulation of our recently developed generalized subsystem vibrational analysis (GSVA) for obtaining intrinsic fragmental vibrations (J Chem Theory Comput 14:2558, 2018) is presented. In contrast to the earlier implementation, which requires the explicit definition of a non-redundant set of internal coordinate parameters to be constructed for the subsystem, the new implementation circumvents this process by employing massless Eckart conditions to the subsystem fragment paired with a Gram-Schmidt orthogonalization to span the same internal vibration space indirectly. This revised version of GSVA (rev-GSVA) can be applied to equilibrium structure as well as transition state structure, and it has been incorporated into the open-source package UniMoVib (https://github.com/zorkzou/UniMoVib). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00214-021-02727-y.

Theoretical Insights into [NHC]Au(I) Catalyzed Hydroalkoxylation of Allenes: A Unified Reaction Valley Approach Study.

Hydroxylation is an effective approach for the synthesis of carbon-oxygen bonds and allylic ethers. The [NHC]Au(I) catalyzed intermolecular hydroalkoxylation of allene was studied at the DFT and Coupled Cluster level of theory. Using the Unified Reaction Valley Approach (URVA), we carry out a comprehensive mechanistic analysis of [NHC]Au(I)-catalyzed and noncatalyzed reactions. The URVA study of several possible reaction pathways reveal that the [NHC]Au(I) catalyst enables the hydroalkoxylation reaction to occur via a two step mechanism based upon the Au ability to switch between π- and σ-complexation. The first step of the mechanism involves the formation of a CO bond after the transition state with no energy penalty. Following the CO bond breakage, the OH bond breaks and CH bond forms during the second step of the mechanism, as the catalyst transforms into the more stable π-Au complex. The URVA results were complemented with local vibrational mode analysis to provide measures of intrinsic bond strength for Au(I)-allene interactions of all stationary points, and NBO analysis was applied in order to observe charge transfer events along the reaction pathway. Overall, the π-Au C═C interactions of the products are stronger than those of the reactants adding to their exothermicity. Our work on the hydroxylation of allene provides new insights for the design of effective reaction pathways to produce allylic ethers and also unravels new strategies to form C-O bonds by activation of C═C bonds.

Describing Polytopal Rearrangement Processes of Octacoordinate Structures. I. Renewed Insights into Fluxionality of the Rhenium Polyhydride Complex ReH5(PPh3)2(Pyridine).

Hydride ligands of transition metal polyhydride complexes with a high coordination number are prone to fluxionality leading to interesting structural dynamics. However, the underlying polytopal rearrangement pathways have been rarely studied. Based on quantum chemical calculations carried out in this work with density functional theory and coupled-cluster theory, two new fluxional mechanisms have been identified for the rhenium polyhydride complex ReH5(PPh3)2(pyridine) to jointly account for two consecutive coalescence events in the variable-temperature NMR spectra upon heating: lateral and basal three-arm turnstile rotation. The frequently cited pseudorotation in ReH5(PPh3)2(pyridine) (Lee et al. Inorg. Chem. 1996, 35, 695) turns out to be a three-step process including two lateral three-arm turnstile steps and one basal turnstile step in between. The new fluxional mechanisms discovered in this work may also exist in other transition metal polyhydrides.

SSnet: A Deep Learning Approach for Protein-Ligand Interaction Prediction.

Computational prediction of Protein-Ligand Interaction (PLI) is an important step in the modern drug discovery pipeline as it mitigates the cost, time, and resources required to screen novel therapeutics. Deep Neural Networks (DNN) have recently shown excellent performance in PLI prediction. However, the performance is highly dependent on protein and ligand features utilized for the DNN model. Moreover, in current models, the deciphering of how protein features determine the underlying principles that govern PLI is not trivial. In this work, we developed a DNN framework named SSnet that utilizes secondary structure information of proteins extracted as the curvature and torsion of the protein backbone to predict PLI. We demonstrate the performance of SSnet by comparing against a variety of currently popular machine and non-Machine Learning (ML) models using various metrics. We visualize the intermediate layers of SSnet to show a potential latent space for proteins, in particular to extract structural elements in a protein that the model finds influential for ligand binding, which is one of the key features of SSnet. We observed in our study that SSnet learns information about locations in a protein where a ligand can bind, including binding sites, allosteric sites and cryptic sites, regardless of the conformation used. We further observed that SSnet is not biased to any specific molecular interaction and extracts the protein fold information critical for PLI prediction. Our work forms an important gateway to the general exploration of secondary structure-based Deep Learning (DL), which is not just confined to protein-ligand interactions, and as such will have a large impact on protein research, while being readily accessible for de novo drug designers as a standalone package.

Comment on "Exploring nature and predicting strength of hydrogen bonds: A correlation analysis between atoms-in-molecules descriptors, binding energies, and energy components of symmetry-adapted perturbation theory".

We evaluate the correlation between binding energy (BE) and electron density ρ(r) at the bond critical point for 28 neutral hydrogen bonds, recently reported by Emamian and co-workers (J. Comput. Chem., 2019, 40, 2868). As an efficient tool, we use local stretching force constant k HB a derived from the local vibrational mode theory of Konkoli and Cremer. We compare the physical nature of BE versus k HB a , and provide an important explanation for cases with significant deviation in the BE- k HB a relation as well as in the BE-ρ(r) correlation. We also show that care has to be taken when different hydrogen bond strength measures are compared. The BE is a cumulative hydrogen bond strength measure while k HB a is a local measure of hydrogen bond strength covering different aspects of bonding. A simplified and unified description of hydrogen bonding is not always possible and needs an in-depth understanding of the systems involved.

Two Novel Palbociclib-Resorcinol and Palbociclib-Orcinol Cocrystals with Enhanced Solubility and Dissolution Rate.

Palbociclib (PAL) is an effective anti-breast cancer drug, but its use has been partly restricted due to poor bioavailability (resulting from extremely low water solubility) and serious adverse reactions. In this study, two cocrystals of PAL with resorcinol (RES) or orcinol (ORC) were prepared by evaporation crystallization to enhance their solubility. The cocrystals were characterized by single crystal X-ray diffraction, Hirshfeld surface analysis, powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Fourier transform infrared and scanning electron microscopy. The intrinsic dissolution rates of the PAL cocrystals were determined in three different dissolution media (pH 1.0, pH 4.5 and pH 6.8), and both cocrystals showed improved dissolution rates at pH 1.0 and pH 6.8 in comparison to the parent drug. In addition, the cocrystals increased the solubility of PAL at pH 6.8 by 2-3 times and showed good stabilities in both the accelerated stability testing and stress testing. The PAL-RES cocrystal also exhibited an improved relative bioavailability (1.24 times) than PAL in vivo pharmacokinetics in rats. Moreover, the in vitro cytotoxicity assay of PAL-RES showed an increased IC50 value for normal cells, suggesting a better biosafety profile than PAL. Co-crystallization may represent a promising strategy for improving the physicochemical properties of PAL with better pharmacokinetics.

Modeling Hydrogen Release from Water with Borane and Alane Catalysts: A Unified Reaction Valley Approach.

The unified reaction valley approach combined with the local vibrational mode and ring puckering analysis is applied to investigate the hydrogen evolution from water in the presence of small hydrides such as BH3, metal hydrides as AlH3, and their derivatives. We studied a series of reactions involving BH3, AlH3, B2H6, Al2H6, and AlH3BH3 with one- and two-water molecules, considering multiple reaction paths. In addition, the influence of the aqueous medium was examined. A general reaction mechanism was identified for most of the reactions. Those that deviate could be associated with unusually high reaction barriers with no hydrogen release. The charge transfer along the reaction path suggests that a viable hydrogen release is achieved when the catalyst adopts the role of a charge donor during the chemical processes. The puckering analysis showed that twistboat and boat forms are the predominant configurations in the case of an intermediate six-membered ring formation, which influences the activation barrier. The local mode analysis was used as a tool to detect the H-H bond formation as well as to probe catalyst regenerability. Based on the correlation between the activation energy and the change in the charge separation for cleaving O-H and B(Al)-H bonds, two promising subsets of reactions could be identified along with prescriptions for lowering the reaction barrier individually with electron-donating/withdrawing substituents.

PyVibMS: a PyMOL plugin for visualizing vibrations in molecules and solids.

Visualizing vibrational motions calculated with different ab initio packages requires dedicated post-processing tools. Here, we present a PyMOL plugin called PyVibMS for visualizing the vibrational motions for both molecular and solid systems calculated by mainstream quantum chemical computer programs including Gaussian, Q-Chem, VASP, and CRYSTAL. Benefiting from the continuing development of the PyMOL platform, PyVibMS provides powerful functionalities and user-friendly interface. PyVibMS was written in Python and its open-source nature makes it flexible and sustainable. As an example, the motions of the Konkoli-Cremer local vibrational modes are shown in this work for the first time. PyVibMS is freely available at https://github.com/smutao/PyVibMS . Graphical abstract In this work, a PyMOL plugin named PyVibMS is developed to visualize molecular and lattice vibrations.