Multimer Embedding Approach for Molecular Crystals up to Harmonic Vibrational Properties.

Accurate calculations of molecular crystals are crucial for drug design and crystal engineering. However, periodic high-level density functional calculations using hybrid functionals are often prohibitively expensive for the relevant systems. These expensive periodic calculations can be circumvented by the usage of embedding methods in which, for instance, the periodic calculation is only performed at a lower-cost level and then monomer energies and dimer interactions are replaced by those of the higher-level method. Herein, we extend such a multimer embedding approach to enable energy corrections for trimer interactions and the calculation of harmonic vibrational properties up to the dimer level. We evaluate this approach for the X23 benchmark set of molecular crystals by approximating a periodic hybrid density functional (PBE0+MBD) by embedding multimers into less expensive calculations using a generalized-gradient approximation functional (PBE+MBD). We show that trimer interactions are crucial for accurately approximating lattice energies within 1 kJ/mol and might also be needed for further improvement of lattice constants and hence cell volumes. Finally, the vibrational properties are already very well captured at the monomer and dimer level, making it possible to approximate vibrational free energies at room temperature within 1 kJ/mol.

"Freedom of design" in chemical compound space: towards rational in silico design of molecules with targeted quantum-mechanical properties.

The rational design of molecules with targeted quantum-mechanical (QM) properties requires an advanced understanding of the structure-property/property-property relationships (SPR/PPR) that exist across chemical compound space (CCS). In this work, we analyze these fundamental relationships in the sector of CCS spanned by small (primarily organic) molecules using the recently developed QM7-X dataset, a systematic, extensive, and tightly converged collection of 42 QM properties corresponding to ≈4.2M equilibrium and non-equilibrium molecular structures containing up to seven heavy/non-hydrogen atoms (including C, N, O, S, and Cl). By characterizing and enumerating progressively more complex manifolds of molecular property space-the corresponding high-dimensional space defined by the properties of each molecule in this sector of CCS-our analysis reveals that one has a substantial degree of flexibility or "freedom of design" when searching for a single molecule with a desired pair of properties or a set of distinct molecules sharing an array of properties. To explore how this intrinsic flexibility manifests in the molecular design process, we used multi-objective optimization to search for molecules with simultaneously large polarizabilities and HOMO-LUMO gaps; analysis of the resulting Pareto fronts identified non-trivial paths through CCS consisting of sequential structural and/or compositional changes that yield molecules with optimal combinations of these properties.

QM7-X, a comprehensive dataset of quantum-mechanical properties spanning the chemical space of small organic molecules.

We introduce QM7-X, a comprehensive dataset of 42 physicochemical properties for ≈4.2 million equilibrium and non-equilibrium structures of small organic molecules with up to seven non-hydrogen (C, N, O, S, Cl) atoms. To span this fundamentally important region of chemical compound space (CCS), QM7-X includes an exhaustive sampling of (meta-)stable equilibrium structures-comprised of constitutional/structural isomers and stereoisomers, e.g., enantiomers and diastereomers (including cis-/trans- and conformational isomers)-as well as 100 non-equilibrium structural variations thereof to reach a total of ≈4.2 million molecular structures. Computed at the tightly converged quantum-mechanical PBE0+MBD level of theory, QM7-X contains global (molecular) and local (atom-in-a-molecule) properties ranging from ground state quantities (such as atomization energies and dipole moments) to response quantities (such as polarizability tensors and dispersion coefficients). By providing a systematic, extensive, and tightly-converged dataset of quantum-mechanically computed physicochemical properties, we expect that QM7-X will play a critical role in the development of next-generation machine-learning based models for exploring greater swaths of CCS and performing in silico design of molecules with targeted properties.

Revised values for the X23 benchmark set of molecular crystals.

We present revised reference values for cell volumes and lattice energies for the widely used X23 benchmark set of molecular crystals by including the effect of thermal expansion. For this purpose, thermally-expanded structures were calculated via the quasi-harmonic approximation utilizing three dispersion-inclusive density-functional approximations. Experimental unit-cell volumes were back-corrected for thermal and zero-point energy effects, allowing now a direct comparison with lattice relaxations based on electronic energies. For the derivation of reference lattice energies, we utilized harmonic vibrational contributions averaged over four density-functional approximations. In addition, the new reference values also take the change in electronic and vibrational energy due to thermal expansion into account. This is accomplished by either utilizing experimentally determined cell volumes and heat capacities, or by relying on the quasi-harmonic approximation. The new X23b reference values obtained this way will enable a more accurate benchmark for the performance of computational methods for molecular crystals.

Reliable and practical computational description of molecular crystal polymorphs.

Reliable prediction of the polymorphic energy landscape of a molecular crystal would yield profound insight into drug development in terms of the existence and likelihood of late-appearing polymorphs. However, the computational prediction of molecular crystal polymorphs is highly challenging due to the high dimensionality of conformational and crystallographic space accompanied by the need for relative free energies to within 1 kJ/mol per molecule. In this study, we combine the most successful crystal structure sampling strategy with the most successful first-principles energy ranking strategy of the latest blind test of organic crystal structure prediction methods. Specifically, we present a hierarchical energy ranking approach intended for the refinement of relative stabilities in the final stage of a crystal structure prediction procedure. Such a combined approach provides excellent stability rankings for all studied systems and can be applied to molecular crystals of pharmaceutical importance.

Adhesion, forces and the stability of interfaces.

Weak molecular interactions (WMI) are responsible for processes such as physisorption; they are essential for the structure and stability of interfaces, and for bulk properties of liquids and molecular crystals. The dispersion interaction is one of the four basic interactions types - electrostatics, induction, dispersion and exchange repulsion - of which all WMIs are composed. The fact that each class of basic interactions covers a wide range explains the large variety of WMIs. To some of them, special names are assigned, such as hydrogen bonding or hydrophobic interactions. In chemistry, these WMIs are frequently used as if they were basic interaction types. For a long time, dispersion was largely ignored in chemistry, attractive intermolecular interactions were nearly exclusively attributed to electrostatic interactions. We discuss the importance of dispersion interactions for the stabilization in systems that are traditionally explained in terms of the "special interactions" mentioned above. System stabilization can be explained by using interaction energies, or by attractive forces between the interacting subsystems; in the case of stabilizing WMIs, one frequently speaks of adhesion energies and adhesive forces. We show that the description of system stability using maximum adhesive forces and the description using adhesion energies are not equivalent. The systems discussed are polyaromatic molecules adsorbed to graphene and carbon nanotubes; dimers of alcohols and amines; cellulose crystals; and alcohols adsorbed onto cellulose surfaces.

First-principles stability ranking of molecular crystal polymorphs with the DFT+MBD approach.

The ability to accurately calculate the relative stabilities of numerous polymorphs of a given molecular crystal is crucial for the success of any molecular crystal structure prediction (CSP) approach. We have recently presented a hierarchical CSP procedure based on van-der-Waals-inclusive density functional theory [Hoja et al., 2018, arXiv:1803.07503], which yields excellent stability rankings for molecular crystals involving rigid molecules, salts, co-crystals, and highly polymorphic drug-like molecules. This approach includes many-body dispersion effects, exact exchange, as well as vibrational free energies. Here, we discuss in detail the impact of these effects on the obtained stability rankings. In addition, we assess the impact of the approximations used in our hierarchical procedure. We show that our procedure is generally robust to 1-2 kJ mol-1 for the systems in the latest CSP blind test but vibrational free energies for crystals involving flexible molecules would benefit from directly including many-body dispersion interactions. In addition, we also discuss the effect of temperature on the structure of molecular crystals and a simple but effective method for estimating anharmonic effects.

Hidden Beneath the Surface: Origin of the Observed Enantioselective Adsorption on PdGa(111).

We unravel the origin of the recently observed striking enantioselectivity of the PdGa(111) surface with respect to the adsorption of a small organic molecule, 9-ethynylphenanthrene, using first-principles calculations. It turns out that the key ingredient to understand the experimental evidence is the appropriate description of van der Waals interactions beyond the widely employed atomic pairwise approximation. A recently developed van der Waals-inclusive density functional method, which encompasses dielectric screening effects, reveals the origin of the experimentally observed enantioselectivity and provides conclusive evidence of chiral recognition on a bimetallic surface driven by dispersion interactions. The incorporation of dielectric screening leads to a renormalization of the dispersion interaction range, allowing for the appropriate weighting of the molecule-substrate interactions at intermediate distances between 2.5 and 5 Å. Our findings have implications for the structure and stability of complex organic/inorganic systems where dielectric screening effects are expected to be of general importance.

Powder diffraction and crystal structure prediction identify four new coumarin polymorphs.

Coumarin, a simple, commodity chemical isolated from beans in 1820, has, to date, only yielded one solid state structure. Here, we report a rich polymorphism of coumarin grown from the melt. Four new metastable forms were identified and their crystal structures were solved using a combination of computational crystal structure prediction algorithms and X-ray powder diffraction. With five crystal structures, coumarin has become one of the few rigid molecules showing extensive polymorphism at ambient conditions. We demonstrate the crucial role of advanced electronic structure calculations including many-body dispersion effects for accurate ranking of the stability of coumarin polymorphs and the need to account for anharmonic vibrational contributions to their free energy. As such, coumarin is a model system for studying weak intermolecular interactions, crystallization mechanisms, and kinetic effects.

Strong Local-Field Enhancement of the Nonlinear Soft-Mode Response in a Molecular Crystal.

The nonlinear response of soft-mode excitations in polycrystalline acetylsalicylic acid (aspirin) is studied with two-dimensional terahertz spectroscopy. We demonstrate that the correlation of CH_{3} rotational modes with collective oscillations of π electrons drives the system into the nonperturbative regime of light-matter interaction, even for a moderate strength of the THz driving field on the order of 50 kV/cm. Nonlinear absorption around 1.1 THz leads to a blueshifted coherent emission at 1.7 THz, revealing the dynamic breakup of the strong electron-phonon correlations. The observed behavior is reproduced by theoretical calculations including dynamic local-field correlations.

Report on the sixth blind test of organic crystal structure prediction methods.

The sixth blind test of organic crystal structure prediction (CSP) methods has been held, with five target systems: a small nearly rigid molecule, a polymorphic former drug candidate, a chloride salt hydrate, a co-crystal and a bulky flexible molecule. This blind test has seen substantial growth in the number of participants, with the broad range of prediction methods giving a unique insight into the state of the art in the field. Significant progress has been seen in treating flexible molecules, usage of hierarchical approaches to ranking structures, the application of density-functional approximations, and the establishment of new workflows and `best practices' for performing CSP calculations. All of the targets, apart from a single potentially disordered Z' = 2 polymorph of the drug candidate, were predicted by at least one submission. Despite many remaining challenges, it is clear that CSP methods are becoming more applicable to a wider range of real systems, including salts, hydrates and larger flexible molecules. The results also highlight the potential for CSP calculations to complement and augment experimental studies of organic solid forms.

Adsorption of glucose, cellobiose, and cellotetraose onto cellulose model surfaces.

Reliable simulation of molecular adsorption onto cellulose surfaces is essential for the design of new cellulose nanocomposite materials. However, the applicability of classical force field methods to such systems remains relatively unexplored. In this study, we present the adsorption of glucose, cellobiose, and cellotetraose on model surfaces of crystalline cellulose Iα and Iß. The adsorption of the two large carbohydrates was simulated with the GLYCAM06 force field. To validate this approach, quantum theoretical calculations for the adsorption of glucose were performed: Equilibrium geometries were studied with density functional theory (DFT) and dispersion-corrected DFT, whereas the adsorption energies were calculated with two standard density functional approximations and five dispersion-containing DFT approaches. We find that GLYCAM06 gives a good account of geometries and, in most cases, accurate adsorption energies when compared to dispersion-corrected DFT energies. Adsorption onto the (100) surface of cellulose Iα is, in general, stronger than onto the (100) surface of cellulose Iß. Contrary to intuition, the adsorption energy is not directly correlated with the number of hydrogen bonds; rather, it is dominated by dispersion interactions. Especially for bigger adsorbates, a neglect of these interactions leads to a dramatic underestimation of adsorption energies.

Is electrostatics sufficient to describe hydrogen-bonding interactions?

The stability and geometry of a hydrogen-bonded dimer is traditionally attributed mainly to the central moiety A-H⋅⋅⋅B, and is often discussed only in terms of electrostatic interactions. The influence of substituents and of interactions other than electrostatic ones on the stability and geometry of hydrogen-bonded complexes has seldom been addressed. An analysis of the interaction energy in the water dimer and several alcohol dimers--performed in the present work by using symmetry-adapted perturbation theory--shows that the size and shape of substituents strongly influence the stabilization of hydrogen-bonded complexes. The larger and bulkier the substituents are, the more important the attractive dispersion interaction is, which eventually becomes of the same magnitude as the total stabilization energy. Electrostatics alone are a poor predictor of the hydrogen-bond stability trends in the sequence of dimers investigated, and in fact, dispersion interactions predict these trends better.