We analyze the performance of the polarizable density embedding (PDE) model-a new multiscale computational approach designed for prediction and rationalization of general molecular properties of large and complex systems. We showcase how the PDE model very effectively handles the use of large and diffuse basis sets that are otherwise questionable-due to electron spill-out effects-in standard embedding models. Based on our analysis, we find the PDE model to be robust and much more systematic than less sophisticated focused embedding models, and thus outline the PDE model as a very efficient and accurate approach to describe the electronic structure of ground and excited states as well as molecular properties of complex, heterogeneous systems.

The polarizable embedding (PE) model is a fragment-based quantum-classical approach aimed at accurate inclusion of environment effects in quantum-mechanical response property calculations. The aim of this tutorial review is to give insight into the practical use of the PE model.Starting from a set of molecular structures and until you arrive at the final property, there are many crucial details to consider in order to obtain trustworthy results in an efficient manner. To lower the threshold for new users wanting to explore the use of the PE model, we describe and discuss important aspects related to its practical use. This includes directions on how to generate input files and how to run a calculation. K E Y W O R D S computational spectroscopy, molecular properties, polarizable embedding, QM/MM, response properties 1 | INTRODUCTION Hybrid quantum-classical approaches for modeling of chemical or biological systems have in recent years gained considerable interest. The reasonfor such popularity of these models relies, to a large degree, on their efficiency and the fact that such models enable calculations on systems of sizes that are otherwise impossible using pure quantum-mechanical methods. The dielectric continuum models belong to the simplest of the quantum-classical approaches, [1,2] and models like the polarizable continuum model [3,4] are today implemented in many of the available electronic-structure programs. In addition, such models are very easy to use: based on a predefined set of atomic radii and the dielectric constant of the solvent, the user can include solvation effects based only on a single calculation. Only one calculation is needed because the dielectric continuum models implicitly include sampling of solvent configurations. On the other hand, it is well-known that the dielectric continuum models possess several drawbacks, such as the inability to model the directionality of specific intermolecular interactions like hydrogen bonding or π-π stacking. Because of this, modeling of environment anisotropies, as found in, for example, protein matrices is lost.Another class of quantum-classical approaches consists of discrete models where the atomistic detail of the environment is kept, that is, models based on the concept of combined quantum mechanics and molecular mechanics (QM/MM). [5][6][7][8] Discrete models, compared to the dielectric continuum models, realistically describe the environment, but at an increased level of both complexity and computational requirements.Regarding the latter point, the increase in computational time is not linked to the discrete nature of the environment as such but rather that

The Dalton Project provides a uniform platform access to the underlying full-fledged quantum chemistry codes Dalton and LSDalton as well as the PyFraME package for automatized fragmentation and parameterization of complex molecular environments. The platform is written in Python and defines a means for library communication and interaction. Intermediate data such as integrals are exposed to the platform and made accessible to the user in the form of NumPy arrays, and the resulting data are extracted, analyzed, and visualized. Complex computational protocols that may, for instance, arise due to a need for environment fragmentation and configuration-space sampling of biochemical systems are readily assisted by the platform. The platform is designed to host additional software libraries and will serve as a hub for future modular software development efforts in the distributed Dalton community.

QM/MM calculations of electronic excitations with diffuse basis sets often have large errors due to spill-out of electrons from the quantum subsystem. The Pauli repulsion of the electrons by the environment has to be included to avoid this. We propose transferable atomic all-electron pseudopotentials that can readily be combined with most MM force fields to avoid electron spill-out. QM/MM excitation energies computed with time-dependent Hartree–Fock and the algebraic diagrammatic construction through second-order are benchmarked against supermolecular calculations to validate these new pseudopotentials. The QM/MM calculations with pseudopotentials give accurate results that are stable with augmentation of the basis set with diffuse functions. We show that the largest contribution to residual deviations from full QM calculations is caused by the missing London dispersion interaction.

The recent development of liquid jet and liquid leaf sample delivery systems allows for accurate measurements of soft X-ray absorption spectra in transmission mode of solutes in a liquid environment. As this type of measurement becomes increasingly accessible, there is a strong need for reliable theoretical methods for assisting in the interpretation of the experimental data. Coupled cluster methods have been extensively developed over the past decade to simulate X-ray absorption in the gas phase. Their performance for solvated species, on the contrary, remains largely unexplored. Here, we investigate the current state of the art of coupled cluster modeling of nitrogen K -edge X-ray absorption of aqueous ammonia and ammonium based on quantum mechanics/molecular mechanics, where both the level of coupled cluster calculations and polarizable embedding are scrutinized. The results are compared to existing experimental data as well as simulations based on transition potential density functional theory.

We present a variant of the algebraic diagrammatic construction (ADC) scheme by combining ADC with the polarizable embedding (PE) model. The presented PE-ADC method is implemented through second and third order and is designed with the aim of performing accurate calculations of excited states in large molecular systems. Accuracy and large-scale applicability are demonstrated with three case studies, and we further analyze the importance of both state-specific and linear-response-type corrections to the excitation energies in the presence of the polarizable environment. We demonstrate how our combined method can be readily applied to study photoinduced biochemical processes as we model the charge-transfer (CT) excitation which is key to the photoprotection mechanism in the dodecin protein with PE-ADC(2). Through direct access to state-of-the-art excited state analysis, we find that the polarizable environment plays a decisive role by significantly increasing the CT character of the electronic excitation in dodecin. PE-ADC is thus suited to decipher photoinduced processes in complex, biomolecular systems at high precision and at reasonable computational cost.

The solvatochromic fluorophore Nile Red, 9-diethylamino-5H-benzo[a]phenoxazine-5-one, is one of the most commonly used stains to enhance contrast of lipid-rich areas of microscopic biosamples. Quite surprisingly, relatively little is known about...

Conjugation of pleuromutilin is an attractive strategy for development of novel antibiotics and the fight against multi-resistant bacteria as the class is associated with low rates of resistance and cross-resistance development. Herein, the preparation of 35 novel (+)-pleuromutilin conjugates is reported. Their design was based on a synthetically more efficient benzyl-adaption of a potent lead, but still relied on the Cu(I)-catalysed alkyne-azide [3+2] cycloaddition for conjugation onto pleuromutilin. Their antibacterial activity was evaluated against the multi-resistant Staphylococcus 2 aureus strain USA300 for which they displayed moderate to excellent activity. Compound 35, bearing a para-benzyladenine substituent proved particularly potent against USA300 as well as additional strains of MRSA and displayed as importantly no cytotoxicity in four mammalian cell lines. Structure-activity relationship analysis revealed that the purine 6-amino is essential for high potency, likely due to strong hydrogen bonding with the RNA backbone of C2469 as suggested by a molecular model based on the MM-GBSA approach. 9 Alkylation of the nucleobases (thymine, adenine, 6-chloropurine and 2-amino-chloropurine) was achieved in the presence of an inorganic base (K2CO3 or NaH) in DMF. The yields for 68-78 were mainly deteriorated by lack of regioselectivity, i.e. formation of the N3 isomer (thymines) or N7 isomer (purines), which in turn also complicated their subsequent separation during Flash Chromatography. The strategy was overall still more efficient and straightforward than our previous approach.The chloropurins 74-78 were converted via nucleophilic aromatic substitution with various amines in anhydrous EtOH to grant 79-86, generally in excellent yields. Compound 87 was prepared via guanidination in accordance with a procedure optimized by Česnek and coworkers. 35 The primary benzylamines 89 and 96-97 were synthesized via two strategies (Scheme 3); the para analogue 89 via standard Gabriel synthesis, which proved highly efficient, simultaneously also granting the phthalimide 88. The second strategy involved reduction of ethynylbenzonitriles with LiAlH4, 36 which also proved efficient, granting the nitriles 94 and 95 as well. Scheme 3.Reagents and conditions: (a) K-phthalimide, DMF, rt.; (b) H2N-NH2  H2O 50-60% w/w, EtOH, 78 o C; (a) Trimethylsilylacetylene, Pd(PPh3)4, CuI, Anh. Piperidine 80 o C; (d) K2CO3, MeOH, rt.; (e) i) 1 M LiAlH4 in THF, THF, -10 o C → rt. ii) H2O, NaOH (sat.).