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Penicillin-binding proteins (PBPs) contribute to bacterial cell wall biosynthesis and are targets of antibacterial agents. Here, we investigated PBP1b inhibition by boronic acid derivatives. Chemical starting points were identified by structure-based virtual screening and aliphatic boronic acids were selected for further investigations. Structure–activity relationship studies focusing on the branching of the boron-connecting carbon and quantum mechanical/molecular mechanical simulations showed that reaction barrier free energies are compatible with fast reversible covalent binding and small or missing reaction free energies limit the inhibitory activity of the investigated boronic acid derivatives. Therefore, covalent labelling of the lysine residue of the catalytic dyad was also investigated. Compounds with a carbonyl warhead and an appropriately positioned boronic acid moiety were shown to inhibit and covalently label PBP1b. Reversible covalent labelling of the catalytic lysine by imine formation and the stabilisation of the imine by dative N–B bond is a new strategy for PBP1b inhibition. Penicillin-binding protein (PBP) 1b is an antibacterial target with a serine-lysine catalytic dyad. Covalent boronic acid inhibitors targeting the serine residue and compounds containing both a boronic acid moiety and a carbonyl group targeting the lysine residue with a concomitant dative N–B bond formation were studied. Structure-activity studies were combined with QM/M free energy calculations to explore the mechanism of covalent inhibition. [ABSTRACT FROM AUTHOR]

β-amyloid (Aβ) peptides form self-organizing fibrils in Alzheimer's disease. The biologically active, toxic Aβ25–35 fragment of the full-length Aβ-peptide forms a stable, oriented filament network on the mica surface with an epitaxial mechanism at the timescale of seconds. While many of the structural and dynamic features of the oriented Aβ25–35 fibrils have been investigated before, the β-strand arrangement of the fibrils and their exact orientation with respect to the mica lattice remained unknown. By using high-resolution atomic force microscopy, here, we show that the Aβ25–35 fibrils are oriented along the long diagonal of the oxygen hexagon of mica. To test the structure and stability of the oriented fibrils further, we carried out molecular dynamics simulations on model β-sheets. The models included the mica surface and a single fibril motif built from β-strands. We show that a sheet with parallel β-strands binds to the mica surface with its positively charged groups, but the C-terminals of the strands orient upward. In contrast, the model with antiparallel strands preserves its parallel orientation with the surface in the molecular dynamics simulation, suggesting that this model describes the first β-sheet layer of the mica-bound Aβ25–35 fibrils well. These results pave the way toward nanotechnological construction and applications for the designed amyloid peptides. [ABSTRACT FROM AUTHOR]

The recent ascent of targeted covalent inhibitors (TCI) in drug discovery brings new opportunities and challenges to quantum chemical reactivity calculations supporting discovery efforts. TCIs typically form a covalent bond with the targeted nucleophilic amino acid side chain. Their reactivity that can be both computed and experimentally measured is therefore one of the key factors in determining inhibitory potency. Calculation of relevant quantum chemical descriptors and corresponding reaction barriers of model reactions represent efficient ways to predict intrinsic reactivities of covalent ligands. A more comprehensive description of covalent ligand binding is offered by mixed quantum mechanical/molecular mechanical (QM/MM) potentials. Reaction mechanisms can be investigated by the exploration of the potential energy surface as a function of suitable reaction coordinates, and free energy surfaces can also be calculated with molecular dynamics based simulations. Here we review the methodological aspects and discuss applications with primary focus on high‐end QM/MM simulations to illustrate the current status of quantum chemical support to covalent inhibitor design. Available QM approaches are suitable to identify likely reaction mechanisms and rate determining steps in the binding of covalent inhibitors. The efficient QM/MM prediction of ligand reactivities complemented with the computational description of the recognition step makes these computations highly useful in covalent drug discovery. [ABSTRACT FROM AUTHOR]

Exact schemes for the embedding of density functional theory (DFT) and wave function theory (WFT) methods into lower-level DFT or WFT approaches are introduced utilizing orbital localization. First, a simple modification of the projector-based embedding scheme of Manby and co-workers [J. Chem. Phys. 140, 18A507 (2014)] is proposed. We also use localized orbitals to partition the system, but instead of augmenting the Fock operator with a somewhat arbitrary level-shift projector we solve the Huzinaga-equation, which strictly enforces the Pauli exclusion principle. Second, the embedding of WFT methods in local correlation approaches is studied. Since the latter methods split up the system into local domains, very simple embedding theories can be defined if the domains of the active subsystem and the environment are treated at a different level. The considered embedding schemes are benchmarked for reaction energies and compared to quantum mechanics (QM)/molecular mechanics (MM) and vacuum embedding. We conclude that for DFT-in-DFT embedding, the Huzinaga-equation-based scheme is more efficient than the other approaches, but QM/MM or even simple vacuum embedding is still competitive in particular cases. Concerning the embedding of wave function methods, the clear winner is the embedding of WFT into low-level local correlation approaches, and WFT-in-DFT embedding can only be more advantageous if a non-hybrid density functional is employed. [ABSTRACT FROM AUTHOR]

We derive a local basis equation which may be used to determine the orbitals of a group of electrons in a system when the orbitals of that group are represented by a group basis set, i.e., not the basis set one would normally use but a subset suited to a specific electronic group. The group orbitals determined by the local basis equation minimize the energy of a system when a group basis set is used and the orbitals of other groups are frozen. In contrast, under the constraint of a group basis set, the group orbitals satisfying the Huzinaga equation do not minimize the energy. In a test of the local basis equation on HCl, the group basis set included only 12 of the 21 functions in a basis set one might ordinarily use, but the calculated active orbital energies were within 0.001 hartree of the values obtained by solving the Hartree–Fock–Roothaan (HFR) equation using all 21 basis functions. The total energy found was just 0.003 hartree higher than the HFR value. The errors with the group basis set approximation to the Huzinaga equation were larger by over two orders of magnitude. Similar results were obtained for PCl3 with the group basis approximation. Retaining more basis functions allows an even higher accuracy as shown by the perfect reproduction of the HFR energy of HCl with 16 out of 21 basis functions in the valence basis set. When the core basis set was also truncated then no additional error was introduced in the calculations performed for HCl with various basis sets. The same calculations with fixed core orbitals taken from isolated heavy atoms added a small error of about 10-4 hartree. This offers a practical way to calculate wave functions with predetermined fixed core and reduced base valence orbitals at reduced computational costs. The local basis equation can also be used to combine the above approximations with the assignment of local basis sets to groups of localized valence molecular orbitals and to derive a priori localized orbitals. An appropriately chosen localization and basis set assignment allowed a reproduction of the energy of n-hexane with an error of 10-5 hartree, while the energy difference between its two conformers was reproduced with a similar accuracy for several combinations of localizations and basis set assignments. These calculations include localized orbitals extending to 4–5 heavy atoms and thus they require to solve reduced dimension secular equations. The dimensions are not expected to increase with increasing system size and thus the local basis equation may find use in linear scaling electronic structure calculations. [ABSTRACT FROM AUTHOR]