Cocrystal Synthesis through Crystal Structure Prediction.

Crystal structure prediction (CSP) is an invaluable tool in the pharmaceutical industry because it allows to predict all the possible crystalline solid forms of small-molecule active pharmaceutical ingredients. We have used a CSP-based cocrystal prediction method to rank ten potential cocrystal coformers by the energy of the cocrystallization reaction with an antiviral drug candidate, MK-8876, and a triol process intermediate, 2-ethynylglyclerol. For MK-8876, the CSP-based cocrystal prediction was performed retrospectively and successfully predicted the maleic acid cocrystal as the most likely cocrystal to be observed. The triol is known to form two different cocrystals with 1,4-diazabicyclo[2.2.2]octane (DABCO), but a larger solid form landscape was desired. CSP-based cocrystal screening predicted the triol-DABCO cocrystal as rank one, while a triol-l-proline cocrystal was predicted as rank two. Computational finite-temperature corrections enabled determination of relative crystallization propensities of the triol-DABCO cocrystals with different stoichiometries and prediction of the triol-l-proline polymorphs in the free-energy landscape. The triol-l-proline cocrystal was obtained during subsequent targeted cocrystallization experiments and was found to exhibit an improved melting point and deliquescence behavior over the triol-free acid, which could be considered as an alternative solid form in the synthesis of islatravir.

Selecting a stable solid form of remdesivir using microcrystal electron diffraction and crystal structure prediction.

Therapeutic options in response to the coronavirus disease 2019 (COVID-19) outbreak are urgently needed. In this communication, we demonstrate how to support selection of a stable solid form of an antiviral drug remdesivir in quick time using the microcrystal electron diffraction (MicroED) technique and a cloud-based and artificial intelligence implemented crystal structure prediction platform. We present the MicroED structures of remdesivir forms II and IV and conclude that form II is more stable than form IV at ambient temperature in agreement with experimental observations. The combined experimental and theoretical study can serve as a template for formulation scientists in the pharmaceutical industry.

Virtual Coformer Screening by Crystal Structure Predictions: Crucial Role of Crystallinity in Pharmaceutical Cocrystallization.

One of the most popular strategies of the optimization of drug properties in the pharmaceutical industry appears to be a solid form changing into a cocrystalline form. A number of virtual screening approaches have been previously developed to allow a selection of the most promising cocrystal formers (coformers) for an experimental follow-up. A significant drawback of those methods is related to the lack of accounting for the crystallinity contribution to cocrystal formation. To address this issue, we propose in this study two virtual coformer screening approaches based on a modern cloud-computing crystal structure prediction (CSP) technology at a dispersion-corrected density functional theory (DFT-D) level. The CSP-based methods were for the first time validated on challenging cases of indomethacin and paracetamol cocrystallization, for which the previously developed approaches provided poor predictions. The calculations demonstrated a dramatic improvement of the virtual coformer screening performance relative to the other methods. It is demonstrated that the crystallinity contribution to the formation of paracetamol and indomethacin cocrystals is a dominant one and, therefore, should not be ignored in the virtual screening calculations. Our results encourage a broad utilization of the proposed CSP-based technology in the pharmaceutical industry as the only virtual coformer screening method that directly accounts for the crystallinity contribution.

Additive and Photochemical Manufacturing of Copper.

In recent years, 3D printing technologies have been extensively developed, enabling rapid prototyping from a conceptual design to an actual product. However, additive manufacturing of metals in the existing technologies is still cost-intensive and time-consuming. Herein a novel platform for low-cost additive manufacturing is introduced by simultaneously combining the laser-induced forward transfer (LIFT) method with photochemical reaction. Using acrylonitrile butadiene styrene (ABS) polymer as the sacrificial layer, sufficient ejection momentum can be generated in the LIFT method. A low-cost continuous wave (CW) laser diode at 405 nm was utilized and proved to be able to transfer the photochemically synthesized copper onto the target substrate. The wavelength-dependent photochemical behaviour in the LIFT method was verified and characterized by both theoretical and experimental studies compared to 1064 nm fiber laser. The conductivity of the synthesized copper patterns could be enhanced using post electroless plating while retaining the designed pattern shapes. Prototypes of electronic circuits were accordingly built and demonstrated for powering up LEDs. Apart from pristine PDMS materials with low surface energies, the proposed method can simultaneously perform laser-induced forward transfer and photochemical synthesis of metals, starting from their metal oxide forms, onto various target substrates such as polyimide, glass and thermoplastics.

Photochemical Copper Coating on 3D Printed Thermoplastics.

3D printing using thermoplastics has become very popular in recent years, however, it is challenging to provide a metal coating on 3D objects without using specialized and expensive tools. Herein, a novel acrylic paint containing malachite for coating on 3D printed objects is introduced, which can be transformed to copper via one-step laser treatment. The malachite containing pigment can be used as a commercial acrylic paint, which can be brushed onto 3D printed objects. The material properties and photochemical transformation processes have been comprehensively studied. The underlying physics of the photochemical synthesis of copper was characterized using density functional theory calculations. After laser treatment, the surface coating of the 3D printed objects was transformed to copper, which was experimentally characterized by XRD. 3D printed prototypes, including model of the Statue of Liberty covered with a copper surface coating and a robotic hand with copper interconnections, are demonstrated using this painting method. This composite material can provide a novel solution for coating metals on 3D printed objects. The photochemical reduction analysis indicates that the copper rust in malachite form can be remotely and photo-chemically reduced to pure copper with sufficient photon energy.

Self-consistent field for fragmented quantum mechanical model of large molecular systems.

Fragment-based linear scaling quantum chemistry methods are a promising tool for the accurate simulation of chemical and biomolecular systems. Because of the coupled inter-fragment electrostatic interactions, a dual-layer iterative scheme is often employed to compute the fragment electronic structure and the total energy. In the dual-layer scheme, the self-consistent field (SCF) of the electronic structure of a fragment must be solved first, then followed by the updating of the inter-fragment electrostatic interactions. The two steps are sequentially carried out and repeated; as such a significant total number of fragment SCF iterations is required to converge the total energy and becomes the computational bottleneck in many fragment quantum chemistry methods. To reduce the number of fragment SCF iterations and speed up the convergence of the total energy, we develop here a new SCF scheme in which the inter-fragment interactions can be updated concurrently without converging the fragment electronic structure. By constructing the global, block-wise Fock matrix and density matrix, we prove that the commutation between the two global matrices guarantees the commutation of the corresponding matrices in each fragment. Therefore, many highly efficient numerical techniques such as the direct inversion of the iterative subspace method can be employed to converge simultaneously the electronic structure of all fragments, reducing significantly the computational cost. Numerical examples for water clusters of different sizes suggest that the method shall be very useful in improving the scalability of fragment quantum chemistry methods.

Single layer of MX3 (M = Ti, Zr; X = S, Se, Te): a new platform for nano-electronics and optics.

A serial of two-dimensional titanium and zirconium trichalcogenides nanosheets MX3 (M = Ti, Zr; X = S, Se, Te) were investigated based on first-principles calculations. The evaluated low cleavage energy indicates that stable two-dimensional monolayers can be exfoliated from their bulk crystals in the experiment. Electronic studies reveal the very rich electronic properties in these monolayers, including metallic TiTe3 and ZrTe3, direct band gap semiconductor, TiS3, and indirect band gap semiconductors, TiSe3, ZrS3 and ZrSe3. The band gaps of all the semiconductors are between 0.57 and 1.90 eV, which implies their potential applications in nano-electronics. In addition, the calculated effective masses demonstrate the highly anisotropic conduction properties for all the semiconductors. Optically, TiS3 and TiSe3 monolayers exhibit good light absorption in the visible and near-infrared region, respectively, indicating their potential applications in optical devices. In particular, the highly anisotropic optical absorption of the TiS3 monolayer suggests it could be used in designing nano-optical waveguide polarizers.

Contributions of Pauli repulsions to the energetics and physical properties computed in QM/MM methods.

Conventional combined quantum mechanical/molecular mechanical (QM/MM) methods lack explicit treatment of Pauli repulsions between the quantum-mechanical and molecular-mechanical subsystems. Instead, classical Lennard-Jones (LJ) potentials between QM and MM nuclei are used to model electronic Pauli repulsion and long-range London dispersion, despite the fact that the latter two are inherently of quantum nature. Use of the simple LJ potential in QM/MM methods can reproduce minimal geometries and energies of many molecular clusters reasonably well, as compared to full QM calculations. However, we show here that the LJ potential cannot correctly describe subtle details of the electron density of the QM subsystem because of the neglect of Pauli repulsions between the QM and MM subsystems. The inaccurate electron density subsequently affects the calculation of electronic and magnetic properties of the QM subsystem. To explicitly consider Pauli interactions with QM/MM methods, we propose a method to use empirical effective potentials on the MM atoms. The test case of the binding energy and magnetic properties of a water dimer shows promising results for the general application of effective potentials to mimic Pauli repulsions in QM/MM calculations.

Computing pKa Values with a Mixing Hamiltonian Quantum Mechanical/Molecular Mechanical Approach.

Accurate computation of the pKa value of a compound in solution is important but challenging. Here, a new mixing quantum mechanical/molecular mechanical (QM/MM) Hamiltonian method is developed to simulate the free-energy change associated with the protonation/deprotonation processes in solution. The mixing Hamiltonian method is designed for efficient quantum mechanical free-energy simulations by alchemically varying the nuclear potential, i.e., the nuclear charge of the transforming nucleus. In pKa calculation, the charge on the proton is varied in fraction between 0 and 1, corresponding to the fully deprotonated and protonated states, respectively. Inspired by the mixing potential QM/MM free energy simulation method developed previously [H. Hu and W. T. Yang, J. Chem. Phys. 2005, 123, 041102], this method succeeds many advantages of a large class of λ-coupled free-energy simulation methods and the linear combination of atomic potential approach. Theory and technique details of this method, along with the calculation results of the pKa of methanol and methanethiol molecules in aqueous solution, are reported. The results show satisfactory agreement with the experimental data.

Liquid water simulations with the density fragment interaction approach.

We reformulate the density fragment interaction (DFI) approach [Fujimoto and Yang, J. Chem. Phys., 2008, 129, 054102.] to achieve linear-scaling quantum mechanical calculations for large molecular systems. Two key approximations are developed to improve the efficiency of the DFI approach and thus enable the calculations for large molecules: the electrostatic interactions between fragments are computed efficiently by means of polarizable electrostatic-potential-fitted atomic charges; and frozen fragment pseudopotentials, similar to the effective fragment potentials that can be fitted from interactions between small molecules, are employed to take into account the Pauli repulsion effect among fragments. Our reformulated and parallelized DFI method demonstrates excellent parallel performance based on the benchmarks for the system of 256 water molecules. Molecular dynamics simulations for the structural properties of liquid water also show a qualitatively good agreement with experimental measurements including the heat capacity, binding energy per water molecule, and the radial distribution functions of atomic pairs of O-O, O-H, and H-H. With this approach, large-scale quantum mechanical simulations for water and other liquids become feasible.

Nearly free electron superatom states of carbon and boron nitride nanotubes.

By first-principles theory we study the nearly free electron (NFE) states of carbon and boron nitride nanotubes. In addition to the well-known π bands, we found a series of one-dimensional (1D) NFE bands with on-axis spatial distributions, which resemble atomic orbitals projected onto a plane. These bands are 1D counterparts of the recently discovered superatom orbitals of 0D fullerenes. In addition to the previously reported lowest energy NFE state with the angular quantum number l = 0 corresponding to s atomic orbital character, we find higher energy NFE bands with l > 0 corresponding to the p, d, etc., orbitals. We show that these atom-like states of nanotubes originate from the many-body screening, which is responsible for the image potential of the parent two-dimensional (2D) graphene or BN sheets. With a model potential that combines the short-range exchange-correlation and the long-range Coulomb interactions, we reproduce the energies and radial wave function profiles of the NFE states from the density functional theory calculations. When the nanotube radius exceeds the radial extent on NFE states, the NFE state energies converge to those of image potential states of the parent 2D molecular sheets. To explore possible applications in molecular electronics that take advantage of the NFE properties of nanotube building blocks, we investigate the modification of NFE states by transverse electric fields, alkali metal encapsulation, and lateral and concentric nanotube dimerization.

Power-law strength-degree correlation from resource-allocation dynamics on weighted networks.

Many weighted scale-free networks are known to have a power-law correlation between strength and degree of nodes, which, however, has not been well explained. We investigate the dynamic behavior of resource-traffic flow on scale-free networks. The dynamical system will evolve into a kinetic equilibrium state, where the strength, defined by the amount of resource or traffic load, is correlated with the degree in a power-law form with tunable exponent. The analytical results agree well with simulations.