We report the first full and efficient implementation of range-separated local hybrid functionals (RSLHs) into the TURBOMOLE program package. This enables the computation of ground-state energies and nuclear gradients as well as excitation energies. Regarding the computational effort, RSLHs scale like regular local hybrid functionals (LHs) with system or basis set size and increase timings by a factor of 2–3 in total. An advanced RSLH, ωLH22t, has been optimized for atomization energies and reaction barriers. It is an extension of the recent LH20t local hybrid and is based on short-range PBE and long-range HF exchange-energy densities, a pig2 calibration function to deal with the gauge ambiguity of exchange-energy densities, and reoptimized B95c correlation. ωLH22t has been evaluated for a wide range of ground-state and excited-state quantities. It further improves upon the already successful LH20t functional for the GMTKN55 main-group energetics test suite, and it outperforms any global hybrid while performing close to the top rung-4 functional, ωB97M-V, for these evaluations when augmented by D4 dispersion corrections. ωLH22t performs excellently for transition-metal reactivity and provides good balance between delocalization errors and left–right correlation for mixed-valence systems, with a somewhat larger bias toward localized states compared to LH20t. It approaches the accuracy of the best local hybrids to date for core, valence singlet and triplet, and Rydberg excitation energies while improving strikingly on intra- and intermolecular charge-transfer excitations, comparable to the most successful range-separated hybrids available.

The aims of this study were to synthesize 14-O-Methylmorphine-6-O-sulfate (14-O-MeM6SU) and examine its opioid properties (potency, affinity, efficacy) in receptor ligand binding and isolated tissues (mouse vas deferens, MVD and rat vas deferens, RVD bioassays). The results were then compared to the parent compounds morphine-6-O-sulfate (M6SU) and morphine, as well as the �- opioid receptor (MOR) selective agonist peptide [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin (DAMGO). An additional objective was to compare the effect of subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) administered 14-O-MeM6SU, M6SU and morphine in thermal nociception, rat tail-flick (RTF) test. In MVD, the EC50 (nM) value was 4.38 for 14-O-MeM6SU, 102.81 for M6SU, 346.63 for morphine and 238.47 for DAMGO. The effect of 14-O-MeM6SU and DAMGO was antagonized by naloxone (NAL) with Ke value 1-2.00 nM. The Emax values (%) were 99.10, 36.87, 42.51 and 96.99 for 14-O-MeM6SU, M6SU, morphine and DAMGO, respectively. In RVD 14-O-MeM6SU and DAMGO but not M6SU or morphine showed agonist activity. In binding experiments the affinity of 14-OMeM6SU, M6SU, morphine and DAMGO for MOR was 1.12, 11.48, 4.37 and 3.24 nM, respectively. The selectivity of 14-O-MeM6SU was κ/μ= 269 and δ/μ= 9. In G-protein activation experiments, 14-O-MeM6SU and DAMGO showed higher Emax values than M6SU or morphine. S.c. or i.c.v-injected 14-O-MeM6SU, M6SU and morphine produced a dose and time-dependent increase in RTF response latency. 14-O-MeM6SU was the most potent. Our results showed that introduction of 14-O-Me in M6SU increased the binding affinity, agonist potency, and most importantly, the intrinsic efficacy (Emax).

TURBOMOLE is a highly optimized software suite for largescale quantum-chemical and materials science simulations of molecules, clusters, extended systems, and periodic solids. TURBOMOLE uses Gaussian basis sets and has been designed with robust and fast quantum-chemical applications in mind, ranging from homogeneous and heterogeneous catalysis to inorganic and organic chemistry and various types of spectroscopy, light− matter interactions, and biochemistry. This Perspective briefly surveys TURBOMOLE's functionality and highlights recent developments that have taken place between 2020 and 2023, comprising new electronic structure methods for molecules and solids, previously unavailable molecular properties, embedding, and molecular dynamics approaches. Select features under development are reviewed to illustrate the continuous growth of the program suite, including nuclear electronic orbital methods, Hartree−Fock-based adiabatic connection models, simplified time-dependent density functional theory, relativistic effects and magnetic properties, and multiscale modeling of optical properties.

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The optimal tuning (OT) of range-separated hybrid (RSH) functionals has been proposed as the currently most accurate DFT-based way to compute the relevant quantities required for charge-transfer processes in organic chromophores used in organic photovoltaics and related fields. The main drawback of OT-RSHs is that the system-specific tuning of the range-separation parameter is not size-consistent. It therefore also lacks transferability, e.g., when considering processes involving orbitals not involved in the tuning or for reactions between different chromophores. Here we show that the recently reported ωLH22t range-separated local hybrid functional provides ionization energies, electron affinities, and fundamental gaps on par with OT-RSH treatments, approaching the quality of GW results, without any need for system-specific tuning. This holds from relevant organic chromophores of varying sizes all the way to atomic electron affinities. ωLH22t also gives excellent outer-valence quasiparticle spectra and is a generally accurate functional for both main-group and transition-metal energetics, as well as for a variety of excitation types. Range-separated local hybrid functionals are suggested as promising new quantum-chemical tools in molecular electronics.