From Germacarbonyl Compounds’ Perspective: Glad to be Formed and Stable in the Real World

Germacarbonyl compounds are the germanium analogs of carbonyl compounds, and they require an inert atmosphere for stability. Making these compounds survive the ambient conditions was not feasible given the lability of the Ge=E bonds (E = O, S, Se, Te). However, the first examples of germacarbonyl compounds synthesized under ambient conditions by taking advantage of dipyrromethene ligand stabilization are detailed here; the isolated compounds are germanones 3-4, germacarboxylic acids 6-7, germaesters 9-10, and germaamides 12-13 with Ge=E bonds (E = S, Se). The germaamides 12-13 can react under atmospheric conditions with copper(I) halides offering air and water stable monomeric 14-15 and dimeric 16-19 copper(I) complexes (halide = Cl, Br, I). Apart from just binding, selectivity was also observed; thiogermaamide 12 and selenogermaamide 13 bind CuCl and CuBr, respectively, when treated with a mixture of copper(I) halides.

Molecular Basis of Class B GPCR Selectivity for the Neuropeptides PACAP and VIP

The related neuropeptides PACAP and VIP, and their shared PAC1, VPAC1 and VPAC2 receptors, regulate a large array of physiological activities in the central and peripheral nervous systems. However, the lack of comparative and molecular mechanistic investigations hinder further understanding of their preferred binding selectivity and function. PACAP and VIP have comparable affinity at the VPAC1 and VPAC2 receptor, but PACAP is 400–1,000 fold more potent than VIP at the PAC1 receptor. A molecular understanding of the differing neuropeptide-receptor interactions and the details underlying the receptor transitions leading to receptor activation are much needed for the rational design of selective ligands. To these ends, we have combined structural information and advanced simulation techniques to study PACAP/VIP binding selectivity, full-length receptor conformation ensembles and transitions of the PACAP/VIP receptor variants and subtypes, and a few key interactions in the orthosteric-binding pocket. Our results reveal differential peptide-receptor interactions (at the atomistic detail) important for PAC1, VPAC1 and VPAC2 receptor ligand selectivity. Using microsecond-long molecular dynamics simulations and the Markov State Models, we have also identified diverse receptor conformational ensembles and microstate transition paths for each receptor, the potential mechanisms underlying receptor open and closed states, and the interactions and dynamics at the transmembrane orthosteric pocket for receptor activation. These analyses reveal important features in class B GPCR structure-dynamics-function relationships, which provide novel insights for structure-based drug discovery.

Binding selectivity of inhibitors toward the first over the second bromodomain of BRD4: theoretical insights from free energy calculations and multiple short molecular dynamics simulations

Hydrogen bonding interactions of waters with BD1/BD2 and inhibitors play significant roles in inhibitor bindings.