The Resolved Mutual Information Function as a Structural Fingerprint of Biomolecular Sequences for Interpretable Machine Learning Classifiers

In the present article we propose the application of variants of the mutual information function as characteristic fingerprints of biomolecular sequences for classification analysis. In particular, we consider the resolved mutual information functions based on Shannon-, Rényi-, and Tsallis-entropy. In combination with interpretable machine learning classifier models based on generalized learning vector quantization, a powerful methodology for sequence classification is achieved which allows substantial knowledge extraction in addition to the high classification ability due to the model-inherent robustness. Any potential (slightly) inferior performance of the used classifier is compensated by the additional knowledge provided by interpretable models. This knowledge may assist the user in the analysis and understanding of the used data and considered task. After theoretical justification of the concepts, we demonstrate the approach for various example data sets covering different areas in biomolecular sequence analysis.     

Picomolar FKBP inhibitors enabled by a single water-displacing methyl group in bicyclic [4.3.1] aza-amides

Methyl groups can have profound effects in drug discovery but the underlying mechanisms are diverse and incompletely understood. Here we report the stereospecific effect of a single, solvent-exposed methyl group in bicyclic [4.3.1] aza-amides, robustly leading to a 2 to 10-fold increase in binding affinity for FK506-binding proteins (FKBPs). This resulted in the most potent and efficient FKBP ligands known to date. By a combination of co-crystal structures, isothermal titration calorimetry (ITC), density-functional theory (DFT), and 3D reference interaction site model (3D-RISM) calculations we elucidated the origin of the observed affinity boost, which was purely entropically driven and relied on the displacement of a water molecule at the protein–ligand–bulk solvent interface. The best compounds potently occupied FKBPs in cells and enhanced bone morphogenic protein (BMP) signaling. Our results show how subtle manipulation of the solvent network can be used to design atom-efficient ligands for difficult, solvent-exposed binding pockets.

Enhancement by displacement. A single methyl group displaces a water molecule from the binding site of FKBPs, resulting in the most potent binders known, outperforming the natural products FK506 and rapamycin in biochemical and cellular assays.     

[{Cp″Co}3(μ3-P)(μ3-PSe)], ein Dreikerncluster mit einem PSe-Liganden

[{Cp″Co}₃(μ₃-P)(μ₃-PSe)], a Trinuclear Cluster with a PSe Ligand The cothermolysis of [Cp″Co(CO)₂] ( 1 ), Cp″ = C₅H₃Bu-1.3, and P₄ gives besides [{Cp″Co}₃(μ₃-P)₂] ( 2 ) the cobalt P_n complexes [{Cp″Co}₄(μ₃-P)₄] ( 3 ) and [{Cp″Co}₂(μ, η^2:2-P₂)₂] ( 4 ). 2 can be oxidized with grey selenium forming [{Cp″Co}₃(μ₃-P)(μ₃-PSe)] ( 5 ) and [{Cp″Co}₃(μ₃-PSe)₂] ( 6 ), complexes with the hitherto unknown PSe ligand. The crystal structure of 5 reveals a trigonal-bipyramidal Co₃P₂ skeleton with one μ₃-PSe ligand.     

Preparation and structural characterization of transition-metal complexes featuring the cymantrenyl(bromo)boryl ligand

In the present paper, we describe the first structural characterization of cymantrenyl(dihalo)borane and report on its use for the synthesis of novel cymantrenylboryl complexes.     

Synthesis and characterization of new iridium photosensitizers for catalytic hydrogen generation from water

Novel phenylazole ligands were applied successfully in the synthesis of cyclometalated iridium(III) complexes of the general formula [Ir(phenylazole)(2)(bpy)]PF(6) (bpy=2,2'-bipyridine). All complexes were fully characterized by NMR, IR, and MS spectroscopic studies as well as by cyclic voltammetry. Three crystal structures obtained by X-ray analysis complemented the spectroscopic investigations. The excited-state lifetimes of the iridium complexes were determined and showed to be in the range of several hundred ns to multiple μs. All obtained iridium complexes were active as photosensitizers in catalytic hydrogen evolution from water in the presence of triethylamine as a sacrificial reducing agent. Applying an in situ formed iron-based water reduction catalyst derived from [HNEt(3)](+) [HFe(3)(CO)(11)](-) and tris[3,5-tris-(trifluoromethyl)-phenyl]phosphine as the ligand, [Ir(2-phenylbenz-oxazole)(2)-(bpy)]PF(6) proved to be the most efficient complex giving a quantum yield of 16% at 440 nm light irradiation.     

Electrochemical texturing of Al-doped ZnO thin films for photovoltaic applications

The processes during chemical and electrochemical etching of Al-doped ZnO are investigated utilizing a scanning flow cell setup with online detection of dissolved Zn ions. The rate of chemical dissolution was found to be a linear function of buffer and proton concentration in near neutral pH solutions according to a transport limited reaction. In contrast, electrochemical etching is limited by the kinetics of the reaction and increases linearly with the imposed current density. Due to this fundamental difference, the dissolution of Zn can be either uniform over the whole surface or highly localized at active sites like grain boundaries. A combined approach of chemical etching and the well-controllable galvanostatic dissolution thus allows a fine adjustment of the ZnO:Al surface texture for applications in silicon thin film photovoltaic cells in order to improve their overall energy conversion efficiency.     

Psoromic acid is a selective and covalent Rab-prenylation inhibitor targeting autoinhibited RabGGTase

Post-translational attachment of geranylgeranyl isoprenoids to Rab GTPases, the key organizers of intracellular vesicular transport, is essential for their function. Rab geranylgeranyl transferase (RabGGTase) is responsible for prenylation of Rab proteins. Recently, RabGGTase inhibitors have been proposed to be potential therapeutics for treatment of cancer and osteoporosis. However, the development of RabGGTase selective inhibitors is complicated by its structural and functional similarity to other protein prenyltransferases. Herein we report identification of the natural product psoromic acid (PA) that potently and selectively inhibits RabGGTase with an IC(50) of 1.3 μM. Structure-activity relationship analysis suggested a minimal structure involving the depsidone core with a 3-hydroxyl and 4-aldehyde motif for binding to RabGGTase. Analysis of the crystal structure of the RabGGTase:PA complex revealed that PA forms largely hydrophobic interactions with the isoprenoid binding site of RabGGTase and that it attaches covalently to the N-terminus of the α subunit. We found that in contrast to other protein prenyltransferases, RabGGTase is autoinhibited through N-terminal (α)His2 coordination with the catalytic zinc ion. Mutation of (α)His dramatically enhances the reaction rate, indicating that the activity of RabGGTase is likely regulated in vivo. The covalent binding of PA to the N-terminus of the RabGGTase α subunit seems to potentiate its interaction with the active site and explains the selectivity of PA for RabGGTase. Therefore, psoromic acid provides a new starting point for the development of selective RabGGTase inhibitors.