A number of diverse bulk properties of the zinc-blende and wurtzite III-V nitrides AlN, GaN, and InN, are predicted from first principles within density-functional theory using the plane-wave ultrasoft pseudopotential method, within both the local density approximation (LDA) and generalized gradient approximation (GGA) to the exchange-correlation functional. Besides structure and cohesion, we study formation enthalpies (a key ingredient in predicting defect solubilities and surface stability), spontaneous polarizations and piezoelectric constants (central parameters for nanostructure modeling), and elastic constants. Our study bears out the relative merits of the two density-functional approaches in describing diverse properties of the III-V nitrides (and of the parent species ${\mathrm{N}}_2,$ Al, Ga, and In). None of the two schemes gives entirely successful results. However, the GGA associated with the multiprojector ultrasoft pseudopotential method slightly outperforms the LDA overall as to lattice parameters, cohesive energies, and formation enthalpies of wurtzite nitrides. This is relevant to the study of properties such as polarization, vibrational frequencies, elastic constants, nonstochiometric substitution, and absorption. A major exception is the formation enthalpy of InN, which is underestimated by the GGA (∼0 vs -0.2 eV).

The Escherichia coli AcrAB-TolC efflux pump is the archetype of the resistance nodulation cell division (RND) exporters from Gram-negative bacteria. Overexpression of RND-type efflux pumps is a major factor in multidrug resistance (MDR), which makes these pumps important antibacterial drug discovery targets. We have recently developed novel pyranopyridine-based inhibitors of AcrB, which are orders of magnitude more powerful than the previously known inhibitors. However, further development of such inhibitors has been hindered by the lack of structural information for rational drug design. Although only the soluble, periplasmic part of AcrB binds and exports the ligands, the presence of the membrane-embedded domain in AcrB and its polyspecific binding behavior have made cocrystallization with drugs challenging. To overcome this obstacle, we have engineered and produced a soluble version of AcrB [AcrB periplasmic domain (AcrBper)], which is highly congruent in structure with the periplasmic part of the full-length protein, and is capable of binding substrates and potent inhibitors. Here, we describe the molecular basis for pyranopyridine-based inhibition of AcrB using a combination of cellular, X-ray crystallographic, and molecular dynamics (MD) simulations studies. The pyranopyridines bind within a phenylalanine-rich cage that branches from the deep binding pocket of AcrB, where they form extensive hydrophobic interactions. Moreover, the increasing potency of improved inhibitors correlates with the formation of a delicate protein- and water-mediated hydrogen bond network. These detailed insights provide a molecular platform for the development of novel combinational therapies using efflux pump inhibitors for combating multidrug resistant Gram-negative pathogens.

Significance: Genome sequencing of a multidrug-resistant clinical isolate of Salmonella Typhimurium from a patient that failed ciprofloxacin therapy revealed a mutation in the efflux pump gene, acrB . Computational modelling revealed that the G288D substitution changed the binding of drugs to the distal binding pocket of AcrB. The mutation was recreated in an unrelated Salmonella strain and also in Escherichia coli ; in both species the efflux of ciprofloxacin was increased by the mutation, explaining its resistant phenotype. This is the first time a substitution within an efflux pump protein has been shown to cause drug resistance. Importantly, the finding that one amino acid change can cause resistance to some drugs, but susceptibility to others, informs those developing new antibiotics.

Pseudomonas aeruginosa infections are becoming increasingly difficult to treat due to intrinsic antibiotic resistance and the propensity of this pathogen to accumulate diverse resistance mechanisms. Hyperexpression of efflux pumps of the Resistance-Nodulation-Cell Division (RND)-type multidrug efflux pumps (e.g., MexAB-OprM), chromosomally encoded by mexAB-oprM, mexCD-oprJ, mexEF-oprN, and mexXY (-oprA) is often detected in clinical isolates and contributes to worrying multi-drug resistance phenotypes. Not all antibiotics are affected to the same extent by the aforementioned RND efflux pumps. The impact of efflux on antibiotic activity varies not only between different classes of antibiotics but also between members of the same family of antibiotics. Subtle differences in physicochemical features of compound-pump and compound-solvent interactions largely determine how compounds are affected by efflux activity. The combination of different high-resolution techniques helps to gain insight into the functioning of these molecular machineries. This review discusses substrate recognition patterns based on experimental evidence and computer simulations with a focus on MexB, the pump subunit of the main RND transporter in P. aeruginosa.

Employing first principles total energy calculations we have studied the behavior of Ga and Al adatoms on the GaAs(001)- $\beta 2$ surface. Beside the adsorption site we identify two diffusion channels that are characterized by different adatom-surface dimer interaction. Both affect the adatom migration: in one channel the adatom jumps across the surface dimers and leaves the dimer bonds intact; in the other one the dimer bonds are broken. The two channels are taken into account to derive effective adatom diffusion barriers. We find a strong diffusion anisotropy for both Al and Ga adatoms and, in agreement with experiments, higher diffusion barriers for Al than for Ga.

Efflux pumps of the resistance nodulation division (RND) superfamily, such as AcrB, make a major contribution to multidrug resistance in Gram-negative bacteria. The development of inhibitors of the RND pumps would improve the efficacy of current and next-generation antibiotics. To date, however, only one inhibitor has been cocrystallized with AcrB. Thus, in silico structure-based analysis is essential for elucidating the interaction between other inhibitors and the efflux pumps. In this work, we used computer docking and molecular dynamics simulations to study the interaction between AcrB and the compound MBX2319, a novel pyranopyridine efflux pump inhibitor with potent activity against RND efflux pumps of Enterobacteriaceae species, as well as other known inhibitors (D13-9001, 1-[1-naphthylmethyl]-piperazine, and phenylalanylarginine-β-naphthylamide) and the binding of doxorubicin to the efflux-defective F610A variant of AcrB. We also analyzed the binding of a substrate, minocycline, for comparison. Our results show that MBX2319 binds very tightly to the lower part of the distal pocket in the B protomer of AcrB, strongly interacting with the phenylalanines lining the hydrophobic trap, where the hydrophobic portion of D13-9001 was found to bind by X-ray crystallography. Additionally, MBX2319 binds to AcrB in a manner that is similar to the way in which doxorubicin binds to the F610A variant of AcrB. In contrast, 1-(1-naphthylmethyl)-piperazine and phenylalanylarginine-β-naphthylamide appear to bind to somewhat different areas of the distal pocket in the B protomer of AcrB than does MBX2319. However, all inhibitors (except D13-9001) appear to distort the structure of the distal pocket, impairing the proper binding of substrates.