Quantum biological insights into CRISPR-Cas9 sgRNA efficiency from explainable-AI driven feature engineering.

CRISPR-Cas9 tools have transformed genetic manipulation capabilities in the laboratory. Empirical rules-of-thumb have been developed for only a narrow range of model organisms, and mechanistic underpinnings for sgRNA efficiency remain poorly understood. This work establishes a novel feature set and new public resource, produced with quantum chemical tensors, for interpreting and predicting sgRNA efficiency. Feature engineering for sgRNA efficiency is performed using an explainable-artificial intelligence model: iterative Random Forest (iRF). By encoding quantitative attributes of position-specific sequences for Escherichia coli sgRNAs, we identify important traits for sgRNA design in bacterial species. Additionally, we show that expanding positional encoding to quantum descriptors of base-pair, dimer, trimer, and tetramer sequences captures intricate interactions in local and neighboring nucleotides of the target DNA. These features highlight variation in CRISPR-Cas9 sgRNA dynamics between E. coli and H. sapiens genomes. These novel encodings of sgRNAs enhance our understanding of the elaborate quantum biological processes involved in CRISPR-Cas9 machinery.

Effect of surface functional groups on MXene conductivity.

We report the in-plane electron transport in the MXenes (i.e., within the MXene layers) as a function of composition using the density-functional tight-binding method, in conjunction with the non-equilibrium Green's functions technique. Our study reveals that all MXene compositions have a linear relationship between current and voltage at lower potentials, indicating their metallic character. However, the magnitude of the current at a given voltage (conductivity) has different trends among different compositions. For example, MXenes without any surface terminations (Ti3C2) exhibit higher conductivity compared to MXenes with surface functionalization. Among the MXenes with -O and -OH termination, those with -O surface termination have lower conductivity than the ones with -OH surface terminations. Interestingly, conductivity changes with the ratio of -O and -OH on the MXene surface. Our calculated I-V curves and their conductivities correlate well with transmission functions and the electronic density of states around the Fermi level. The surface composition-dependent conductivity of the MXenes provides a path to tune the in-plane conductivity for enhanced pseudocapacitive performance.

Accelerating the density-functional tight-binding method using graphical processing units.

Acceleration of the density-functional tight-binding (DFTB) method on single and multiple graphical processing units (GPUs) was accomplished using the MAGMA linear algebra library. Two major computational bottlenecks of DFTB ground-state calculations were addressed in our implementation: the Hamiltonian matrix diagonalization and the density matrix construction. The code was implemented and benchmarked on two different computer systems: (1) the SUMMIT IBM Power9 supercomputer at the Oak Ridge National Laboratory Leadership Computing Facility with 1-6 NVIDIA Volta V100 GPUs per computer node and (2) an in-house Intel Xeon computer with 1-2 NVIDIA Tesla P100 GPUs. The performance and parallel scalability were measured for three molecular models of 1-, 2-, and 3-dimensional chemical systems, represented by carbon nanotubes, covalent organic frameworks, and water clusters.

Hydroxide Anion Transport in Covalent Organic Frameworks.

Hydroxide anion transport is essential for alkaline fuel cells, but hydroxide anion has an inherently low conductivity owing to its small diffusion coefficient and high mass. Ordered open channels found in covalent organic frameworks are promising as pathways to enable hydroxide anion transport, but this remains to be explored. Here we report designed synthesis of anionic covalent organic frameworks that promote hydroxide anion transport across the one-dimensional channels. Engineering cationic chains with imidazolium termini onto the pore walls self-assembles a supramolecular interface of single-file hydroxide anion chains in the channels. The frameworks facilitate hydroxide anion transport to achieve an exceptional conductivity of 1.53 × 10-2 S cm-1 at 80 °C, which is 2-6 orders of magnitude higher than those of linear polymers and other porous frameworks. Impedance spectroscopy at different temperatures and studies on deuterated samples reveal that hydroxide anions transport via a proton-exchange hopping mechanism. These results open a way to design framework materials for energy conversions via engineering an anionic interface.

Encapsulation of Aromatic Guests in the Bisporphyrin Cavity of a Double-Stranded Spiroborate Helicate: Thermodynamic and Kinetic Studies and the Encapsulation Mechanism.

A double-stranded spiroborate helicate bearing a bisporphyrin unit in the middle forms an inclusion complex with electron-deficient aromatic guests that are sandwiched between the porphyrins. In the present study, we systematically investigated the effects of size, electron density, and substituents of a series of aromatic guests on inclusion complex formations within the bisporphyrin. The thermodynamic and kinetic behaviors during the guest-encapsulation process were also investigated in detail. The guest-encapsulation abilities in the helicate increased with the increasing core sizes of the electron-deficient aromatic guests and decreased with the increasing bulkiness and number of substituents of the guests. Among the naphthalenediimide derivatives, those with bulky N-substituents at both ends hardly formed an inclusion complex. Instead, they formed a [2]rotaxane-like inclusion complex through the water-mediated dynamic B-O bond cleavage/reformation of the spiroborate groups of the helicate, which enhanced the conformational flexibility of the helicate to enlarge the bisporphyrin cavity and form an inclusion complex. Based on the X-ray crystal structure of a unique pacman-like 1:1 inclusion complex between the helicate and an ammonium cation as well as the molecular dynamics simulation results, a plausible mechanism for the inclusion of a planar aromatic guest within the helicate is also proposed.

Methane Adsorption on Heteroatom-Modified Maquettes of Porous Carbon Surfaces.

Experimental and theoretical studies disagree on the energetics of methane adsorption on carbon materials. However, this information is critical for the rational design and optimization of the structure and composition of adsorbents for natural gas storage. The delicate nature of dispersion interactions, polarization of both the adsorbent and the adsorbate, interplay between H-bonding and tetrel bonding, and induced dipole/Coulomb interactions inherent to methane physisorption require computational treatment at the highest possible level of theory. In this study, we employed the smallest reasonable computational model, a maquette of porous carbon surfaces with a central site for substitution and methane binding. The most accurate predictions of methane adsorption energetics were achieved by electron-correlated molecular orbital theory CCSD(T) and hybrid density functional theory MN15 calculations employing a saturated, all-electron basis set. The characteristic geometry of methane adsorption on a carbon surface ("lander approach") arises due to bonding interactions of the adsorbent π-system with the proximal H-C bonds of methane, in addition to tetrel bonding between the antibonding orbital of the distal C-H bond and the central atom of the maquette (C, B, or N). The polarization of the electron density, structural deformations, and the comprehensive energetic analysis clearly indicate a ∼3 kJ mol-1 preference for methane binding on the N-substituted maquette. The B-substituted maquette showed a comparable or lower binding energy than the unsubstituted, pure C model, depending on the level of theory employed. The calculated thermodynamic results indicate a strategy for incorporating electron-enriched substitutions (e.g., N) into carbon materials as a way to increase methane storage capacity over electron-deficient (e.g., B) modifications. The thermochemical analysis was revised for establishing a conceptual agreement between the experimental isosteric heat of adsorption and the binding enthalpies from statistical thermodynamics principles.

Density-Functional Tight-Binding Parameters for Bulk Zirconium: A Case Study for Repulsive Potentials.

Density-functional tight-binding (DFTB) parameters are presented for the simulation of the bulk phases of zirconium. Electronic parameters were obtained using a band structure fitting strategy, while two-center repulsive potentials were created by particle swarm optimization. As objective functions for the repulsive potential fitting, we employed the Birch-Murnaghan equations of state for hexagonal close-packed (HCP), body-centered cubic (BCC) and ω phases of Zr from density-functional theory (DFT). When fractional atomic coordinates are not allowed to change in the generation of the equation-of-state curves, long-range repulsive DFTB potentials are able to almost perfectly reproduce equilibrium structures, relative DFT energies of the bulk phases, and bulk moduli. However, the same potentials lead to artifacts in the DFTB potential energy surfaces when atom positions in the unit cell are allowed to fully relax during the change of unit cell parameters. Conventional short-range repulsive DFTB potentials, while inferior in their ability to reproduce DFT bulk energetics, are able to correctly reproduce the qualitative shape of the DFT potential energy surfaces, including the location of global minima, and can therefore be considered more transferable.

Nature of Reactive Hydrogen for Ammonia Synthesis over a Ru/C12A7 Electride Catalyst.

Recently, there have been renewed interests in exploring new catalysts for ammonia synthesis under mild conditions. Electride-based catalysts are among the emerging ones. Ruthenium particles supported on an electride composed of a mixture of calcium and aluminum oxides (C12A7) have attracted great attention for ammonia synthesis due to their facile ability in activating N2 under ambient pressure. However, the exact nature of the reactive hydrogen species and the role of electride support still remain elusive for this catalytic system. In this work, we report for the first time that the surface-adsorbed hydrogen, rather than the hydride encaged in the C12A7 electride, plays a major role in ammonia synthesis over the Ru/C12A7 electride catalyst with the aid of in situ neutron scattering techniques. Combining in situ neutron diffraction, inelastic neutron spectroscopy, density functional theory (DFT) calculation, and temperature-programmed reactions, the results provide direct evidence for not only the presence of encaged hydrides during ammonia synthesis but also the strong thermal and chemical stability of the hydride species in the Ru/C12A7 electride. Steady state isotopic transient kinetic analysis (SSITKA) of ammonia synthesis showed that the coverage of reactive intermediates increased significantly when the Ru particles were promoted by the electride form (coverage up to 84%) of the C12A7 support rather than the oxide form (coverage up to 15%). Such a drastic change in the intermediate coverage on the Ru surface is attributed to the positive role of electride support where the H2 poisoning effect is absent during ammonia synthesis over Ru. The finding of this work has significant implications for understanding catalysis by electride-based materials for ammonia synthesis and hydrogenation reactions in general.

Recent developments in the general atomic and molecular electronic structure system.

A discussion of many of the recently implemented features of GAMESS (General Atomic and Molecular Electronic Structure System) and LibCChem (the C++ CPU/GPU library associated with GAMESS) is presented. These features include fragmentation methods such as the fragment molecular orbital, effective fragment potential and effective fragment molecular orbital methods, hybrid MPI/OpenMP approaches to Hartree-Fock, and resolution of the identity second order perturbation theory. Many new coupled cluster theory methods have been implemented in GAMESS, as have multiple levels of density functional/tight binding theory. The role of accelerators, especially graphical processing units, is discussed in the context of the new features of LibCChem, as it is the associated problem of power consumption as the power of computers increases dramatically. The process by which a complex program suite such as GAMESS is maintained and developed is considered. Future developments are briefly summarized.

Topology-Templated Synthesis of Crystalline Porous Covalent Organic Frameworks.

A strategy is presented for the synthesis of crystalline porous covalent organic frameworks via topology-templated polymerization. The template is based on imine-linked frameworks and their (001) facets seed the C=C bond formation reaction to constitute 2D sp2 carbon-conjugated frameworks. This strategy is applicable to templates with different topologies, enables designed synthesis of frameworks that cannot be prepared via direct polymerization, and creates a series of sp2 carbon frameworks with tetragonal, hexagonal, and kagome topologies. The sp2 carbon frameworks are highly luminescent even in the solid state and exhibit topology-dependent π transmission and exciton migration; these key fundamental π functions are unique to sp2 carbon-conjugated frameworks and cannot be accessible by imine-linked frameworks, amorphous analogues, and 1D conjugated polymers. These results demonstrate an unprecedented strategy for structural and functional designs of covalent organic frameworks.

Chiral-selective etching effects on carbon nanotube growth at edge carbon atoms.

Chemical vapor deposition (CVD) utilizing metal cluster nanoparticle catalysts is commonly used to synthesize carbon nanotubes (CNT), with oxygen-containing species such as water or alcohol included in the feedstock for enhanced yield. However, the etching effect of these additives on the growth mechanism has rarely been investigated, despite evidence suggesting that etching potentially affects the chirality distribution of product CNTs. We used quantum chemical methods to study how water-based etchant radicals (OH and H) may enhance the chiral selectivity during CVD growth using CNT cap models. Chemical reactivities of the caps with the etchant radicals were evaluated using density functional theory (DFT). It was found that the reactivities on the cap edges correlate with the chirality of the caps. These results suggest that proper selection of etchant species can provide opportunities for selective chirality control of the product CNTs. © 2018 Wiley Periodicals, Inc.

The helix-inversion mechanism in double-stranded helical oligomers bridged by rotary cyclic boronate esters.

Attracted by the numerous regulatory functions of double-helical biopolymers such as DNA, many researchers have synthesized various double-helical systems. A recently synthesized double-stranded helical oligomer covalently bridged by rotary boronate esters (BBDD) was shown to undergo helix-inversion that might serve as platform to design rotor systems. However, the detailed helix-inversion mechanism could not be investigated experimentally. Direct molecular dynamics simulations based on density-functional tight-binding energies and gradients computed on-the-fly reveal that disentanglement to the unraveled form and following exchange of the twisted terminal trimethylsilyl (TMS) groups are prerequisites for the observed helix-inversion. The potential of mean force confirms that the originally assumed "concurrent" rotation of the boronate esters and the helix-inversion involves shorter time scale "step-wise" processes, triggered by the disentanglement and exchange of the TMS groups. These results indicate that inversion dynamics of double-helical molecules such as BBDD may be controllable by chemical fine-tuning of the terminal groups. © 2019 Wiley Periodicals, Inc.

Structural transformations of graphene exposed to nitrogen plasma: quantum chemical molecular dynamics simulations.

Nitrogen-doped graphene (N-graphene) has been intensively studied for tailoring the electronic property of the graphene, because different nitrogen configurations influence the electronic properties of N-graphene in different ways. However, atomically precise control of the nitrogen configurations during the doping process remains a challenge in the synthesis of N-graphene. Moreover, additional structural transformations of the graphene carbon network structure as a side-effect of plasma doping are little understood and are as of yet uncontrollable. Therefore, we theoretically investigated the nitrogen doping process of graphene for a range of nitrogen atom incident kinetic energies in nonequilibrium quantum chemical molecular dynamics (QM/MD) simulations. We observed and characterized prominent configurations of N-containing graphene. In analogy to similar, earlier studies of graphene plasma hydrogenation, we observed an Eley-Rideal associative desorption mechanism during the graphene plasma nitrogenation, producing molecular nitrogen. Especially for graphitic-N (Gr-N) and Stone-Wales-defect-N (SW-N) configurations, which are frequently observed in experimental studies, we discovered two typical chemical reaction mechanisms which were well categorized by two key processes: adsorption of primary nitrogen dopant and collision with a secondary nitrogen dopant. We discussed effects of the incident nitrogen energy on the formation mechanism, and propose a method to generate of Gr-N and SW-N configurations selectively by tuning the conditions with respect to the two key formation processes.

Nonadiabatic excited-state intramolecular proton transfer in 3-hydroxyflavone: S2 state involvement via multi-mode effect.

The excited-state intramolecular proton transfer process in 3-hydroxyflavone is investigated based on the computed structural parameters and energetics of stationary points of vibronically coupled S1-S2 potential energy surfaces. A conical intersection close to the Franck-Condon point on S1 is identified. The minimum energy of the conical intersection is found to be near-degenerate with the equilibrium minimum of S2. Quantum nuclear wavepacket simulations revealed a small population transfer from the "bright" S1 to "dark" S2 on a time scale shorter than the O-H stretching vibrational period. Such a nonadiabatic transition opens up the possibility of new photophysical and photochemical pathways, including the proton transfer via S2.

Conformational dynamics of human protein kinase CK2α and its effect on function and inhibition.

Protein kinase, casein kinase II (CK2), is ubiquitously expressed and highly conserved protein kinase that shows constitutive activity. It phosphorylates a diverse set of proteins and plays crucial role in several cellular processes. The catalytic subunit of this enzyme (CK2α) shows remarkable flexibility as evidenced in numerous crystal structures determined till now. Here, using analysis of multiple crystal structures and long timescale molecular dynamics simulations, we explore the conformational flexibility of CK2α. The enzyme shows considerably higher flexibility in the solution as compared to that observed in crystal structure ensemble. Multiple conformations of hinge region, located near the active site, were observed during the dynamics. We further observed that among these multiple conformations, the most populated conformational state was inadequately represented in the crystal structure ensemble. The catalytic spine, was found to be less dismantled in this state as compared to the "open" hinge/αD state crystal structures. The comparison of dynamics in unbound (Apo) state and inhibitor (CX4945) bound state exhibits inhibitor induced suppression in the overall dynamics of the enzyme. This is especially true for functionally important glycine-rich loop above the active site. Together, this work gives novel insights into the dynamics of CK2α in solution and relates it to the function. This work also explains the effect of inhibitor on the dynamics of CK2α and paves way for development of better inhibitors.

Light-Emitting Covalent Organic Frameworks: Fluorescence Improving via Pinpoint Surgery and Selective Switch-On Sensing of Anions.

Covalent organic frameworks (COFs) offer ordered π structures that are useful for developing light-emitting materials. However, most COFs are weak in luminescence. Here we report the conversion of less emissive COFs into light-emitting materials via a pinpoint surgery on the pore walls. Deprotonation of the N-H bond to form an anionic nitrogen species in the hydrazone linkage can eliminate the nitrogen-related fluorescence quenching pathway. The resulting COF enhances the fluorescence in a linear proportion to the progress of deprotonation, achieving a 3.8-fold improved emission. This pinpoint N-H cleavage on the pore walls can be driven only by the fluoride anion while other halogen anions, including chloride, bromide, and iodide, remain inactive, enabling the selective fluorescence switch-on sensing of the fluoride anion at a ppb level.

Inducing regioselective chemical reactivity in graphene with alkali metal intercalation.

First principles calculations demonstrate that alkali metal atoms, intercalated between metal substrates and adsorbed graphene monolayers, induce localised regions of increased reactivity. The extent of this localisation is proportional to the size of the alkali atom and the strength of the graphene-substrate interaction. Thus, larger alkali atoms are more effective (e.g. K > Na > Li), as are stronger-interacting substrates (e.g. Ni > Cu). Despite the electropositivity of these alkali metal adsorbates, analysis of charge transfer between the alkali metal, the substrate and the adsorbed graphene layer indicates that charge transfer does not give rise to the observed regioselective reactivity. Instead, the increased reactivity induced in the graphene structure is shown to arise from the geometrical distortion of the graphene layer imposed by the intercalated adsorbed atom. We show that this strategy can be used with arbitrary adsorbates and substrate defects, provided such structures are stable, towards controlling the mesoscale patterning and chemical functionalisation of graphene structures.

Theoretical Prediction and Analysis of the UV/Visible Absorption and Emission Spectra of Chiral Carbon Nanorings.

UV/vis absorption and emission spectra of recently synthesized chiral carbon nanorings were simulated using first-principles-based molecular dynamics and time-dependent density functional theory (TD-DFT). The chiral carbon nanorings are derivatives of the [ n]cycloparaphenylene ([ n]CPP) macrocycles, containing an acene unit such as naphthalene, ([ n]CPPN), anthracene ([ n]CPPA), and tetracene ([ n]CPPT), in addition to n paraphenylene units. In order to study the effect of increasing molecular size on absorption and emission spectra, we investigated the cases where n = 6 and 8. Frontier molecular orbital analysis was carried out to give insight into the degree of excitation delocalization and its relationship to the predicted absorption spectra. The lowest excited singlet state S1 corresponds to a HOMO-LUMO π-π* transition, which is allowed in all chiral carbon nanorings due to lack of molecular symmetry, in contrast to the forbidden HOMO-LUMO transition in the symmetric [ n]CPP molecules. The S1 absorption peak exhibits a blue-shift with increasing number of paraphenylene units in particular for [ n]CPPN and [ n]CPPA and less so in the case of [ n]CPPT. In the case of CPPN and CPPA, the transition density is mainly localized over a semicircle of the macrocycle with the acene unit in its center but is strongly localized on the tetracene unit in the case of CPPT. Molecular dynamics simulations performed on the excited state potential energy surfaces reveal red-shifted emission of these chiral carbon nanorings when the size of the π-conjugated acene units is increased, although the characteristic [ n]CPP blue-shift with increasing paraphenylene unit number n remains apparent. The anomalous emission blue-shift is caused by the excited state bending and torsional motions that stabilize the π HOMO and destabilize the π* LUMO, resulting in an increasing HOMO-LUMO gap.

Quantum chemical replica-exchange umbrella sampling molecular dynamics simulations reveal the formation mechanism of iron phthalocyanine from iron and phthalonitrile.

Phthalocyanine (Pc) and its metal complexes (MPcs) have been used industrially since their discovery in the early 20th century. The phthalonitrile (PN) method is a well-known synthesis method in which Pc or MPc can be afforded by heating a mixture of PN and metal powders over 280 °C with only moderate yield. However, the formation mechanism of the phthalocyanines and the intermediate stages of this seemingly simple reaction have yet to be fully understood. To study this mechanism computationally, we carried out quantum chemical molecular dynamics (MD) simulations based on the density-functional tight-binding (DFTB) method, applying the replica-exchange umbrella sampling (REUS) method, starting from four PN molecules and one iron atom. The DFTB-REUS-MD simulations successfully yielded FePc, and a metastable structure very similar to FePc but with a reactive nitrene unit was also identified that might explain the incomplete conversion of the reactants into FePc. Analysis of the MD trajectories reveals a three-step FePc formation mechanism for the PN method.

Keiji Morokuma (1934-2017).

Keiji Morokuma, William Henry Emerson Professor Emeritus of Emory University and Research Leader at the Fukui Institute for Fundamental Chemistry, Kyoto University, passed away at the age of 83 on November 27, 2017. Morokuma made numerous contributions to theoretical methodologies for the determination of reaction mechanisms and the understanding of intermolecular interactions.