Bridging the length and time scales: from ab initio electronic structure calculations to macroscopic proportions

Density functional theory (DFT) primarily provides a good description of the electronic structure. Thus, DFT primarily deals with length scales as those of a chemical bond, i.e. 10^-10 meter, and with time scales of the order of atomic vibrations, i.e. 10^-13 seconds. However, several interesting phenomena happen and/or become observable on different scales, namely meso- or macroscopic lengths and on time scales of seconds or even minutes. To bridge the gap between 10^-13 seconds and a second or between 10^-10 meter and 10 and more nano meters is one of the important challenges we are facing today. In this paper we show how we are overcoming these time and size problems for the example of crystal growth and the evolution of nano-scale structures. The key is a kinetic Monte Carlo approach with detailed input from DFT calculations of the relevant atomistic processes.Comment: 13 pages, 5 figures, to be published in Comments on Condens. Matt. Phys. (1998). Other related publications can be found at http://www.rz-berlin.mpg.de/th/paper.htm

Ab-initio study of the anomalies in the He atom scattering spectra of H/Mo(110) and H/W(110)

Helium atom scattering (HAS) studies of the H-covered Mo(110) and W(110) surfaces reveal a twofold anomaly in the respective dispersion curves. In order to explain this unusual behavior we performed density functional theory calculations of the atomic and electronic structure, the vibrational properties, and the spectrum of electron-hole excitations of those surfaces. Our work provides evidence for hydrogen adsorption induced Fermi surface nesting. The respective nesting vectors are in excellent agreement with the HAS data and recent angle resolved photoemission experiments of the H-covered alloy system Mo_0.95Re_0.05(110). Also, we investigated the electron-phonon coupling and discovered that the Rayleigh phonon frequency is lowered for those critical wave vectors. Moreover, the smaller indentation in the HAS spectra can be clearly identified as a Kohn anomaly. Based on our results for the susceptibility and the recently improved understanding of the He scattering mechanism we argue that the larger anomalous dip is due to a direct interaction of the He atoms with electron-hole excitations at the Fermi level.Comment: RevTeX, 32 pages, 17 figures, submitted to Phys. Rev.

Anomalies in He atom scattering spectra of the H-covered Mo(110) and W(110) surfaces

Helium atom scattering (HAS) studies of the H-covered Mo(110) and W(110) surfaces reveal a twofold anomaly in the respective dispersion curves. In order to explain this unusual behavior we performed density-functional theory calculations of the atomic and electronic structure, the vibrational properties, and the electronic susceptibility of those surfaces. Our work provides evidence for hydrogen adsorption induced Fermi-{}surface nesting. The respective nesting vectors are in excellent agreement with the HAS data and recent angle resolved photoemission experiments of the H-covered alloy system Mo_0.95Re_0.05(110). Also, we investigated the electron-phonon coupling and discovered that the Rayleigh phonon frequency is lowered for those critical wave vectors compared to the clean surfaces. Moreover, the smaller indentation in the HAS spectra can be clearly identified as a Kohn anomaly. Based on our results for the susceptibility and the recently improved understanding of the He scattering mechanism we argue that the larger anomalous dip is due to electron-hole excitations by the He scattering.Comment: 7 pages, RevTeX, 7 figure

Enhanced electron-phonon coupling at the Mo and W(110) surfaces induced by adsorbed hydrogen

The possible occurrence of either a charge-density-wave or a Kohn anomaly is governed by the presence of Fermi-surface nesting and the subtle interaction of electrons and phonons. Recent experimental and theoretical investigations suggest such an effect for the hydrogen covered Mo and W(110) surfaces. Using density-functional theory we examine the electronic structure and the electron-phonon coupling of these systems. Besides good agreement with the experimental phonon frequencies our study provides a characterization and quantitative analysis of an unusual scenario determining the electronic, vibrational, and structural properties of these surfaces.Comment: 4 Pages, RevTe

Interaction of antibacterial compounds with RND efflux pumps in Pseudomonas aeruginosa

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

Advanced Computational Methods in Molecular Medicine

The dauntingly complex functioning of human cells is often the outcome of several molecular processes. Understanding such processes is crucial for modern drug discovery, defining interaction cascades, assessing the effects of mutations changes in local concentrations of ligands, and so forth. Computational methods, from systems biology to bioinformatics and molecular simulation, allow to access features difficult or impossible to be measured. Models (if properly validated against experimental data) help understand the intricate molecular mechanisms of life processes. Bolstering the predictive power of these models calls upon the computational biologist to improve algorithms and methods. This issue reports on procedures and on applications facing current challenges in computational biology.Modern biological sciences are becoming more and more multidisciplinary. At the same time, theoretical and computational approaches gain in reliability and their field of application widens. O. Fisette at al. discuss recent advances in the areas of solution nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics (MD) simulations that were made possible by the synergistic combination of both methods.Interaction of proteins is of vital importance for many cellular processes and when altered may cause significant health problems, thus the availability of reliable tools to predict and study the determinants of protein-protein interactions is needed. In this regard, X. -Y. Meng et al. present a newly adapted, computationally efficient Brownian Dynamics- (BD-) based protein docking method for predicting native protein complexes. The approach includes global BD conformational sampling, compact complex selection, and local energy minimization. A shell-based grid force field represents the receptor protein and solvation effects, partially considering protein flexibility.Hybrid quantum mechanics/molecular mechanics (QM/MM) calculations are routinely used to study quantum mechanical processes in biological systems. J. Kang et al. present a review paper describing an UNIX shell-based interface program connecting two widely used QM and MM calculation engines, GAMESS and AMBER. The tool was used to investigate a metalloenzyme, azurin, and PU.1-DNA complex and mechanisms of hydrolysis (editing reaction) in leucyl-tRNA synthetase complexed with the mis-aminoacylated tRNALeu. The authors investigate the influence of environmental effects on the electronic structure.Electron transfer in proteins constitutes key steps in several biological processes, ranging from photosynthesis to aerobic respiration. T. Hayashi and A. Stuchebrukhov investigate electron tunneling in NADH : ubiquinone oxidoreductase (Complex I), a key enzyme in cellular respiration as an entry point of the electron transport chain of mitochondria and bacteria, by evaluating the transition flux between donor and acceptor at atomistic resolution. The study suggests that the diffusion of internal water molecules dynamically controls tunneling efficiency

RND efflux pumps: structural information translated into function and inhibition mechanisms

Efflux pumps of the Resistance Nodulation Division (RND) superfamily play a major role in the intrinsic and acquired resistance of Gram-negative pathogens to antibiotics. Moreover, they are largely responsible for multi-drug resistance (MDR) phenomena in these bacteria. The last decade has seen a sharp increase in the number of experimental and computational studies aimed at understanding their functional mechanisms. Most of these studies focused on the RND drug/proton antiporter AcrB, part of the AcrAB-TolC efflux pump actively recognizing and expelling noxious agents from the interior of bacteria. These studies have been focused on the dynamical interactions between AcrB and its substrates and inhibitors, on the details of the proton translocation mechanisms, and on the way AcrB assembles with protein partners to build up a functional pump. In this review we summarize these advances focusing on the role of AcrB

Perturbed structural dynamics underlie inhibition and altered efflux of the multidrug resistance pump AcrB

Resistance–nodulation–division efflux pumps play a key role in inherent and evolved multidrug resistance in bacteria. AcrB, a prototypical member of this protein family, extrudes a wide range of antimicrobial agents out of bacteria. Although high-resolution structures exist for AcrB, its conformational fluctuations and their putative role in function are largely unknown. Here, we determine these structural dynamics in the presence of substrates using hydrogen/deuterium exchange mass spectrometry, complemented by molecular dynamics simulations, and bacterial susceptibility studies. We show that an efflux pump inhibitor potentiates antibiotic activity by restraining drug-binding pocket dynamics, rather than preventing antibiotic binding. We also reveal that a drug-binding pocket substitution discovered within a multidrug resistant clinical isolate modifies the plasticity of the transport pathway, which could explain its altered substrate efflux. Our results provide insight into the molecular mechanism of drug export and inhibition of a major multidrug efflux pump and the directive role of its dynamics

Point Mutation I261M Affects the Dynamics of BVDV and its Interaction with Benzimidazole Antiviral 227G

Bovine viral diarrhea virus (BVDV) is a Pestivirus of the Flaviviridae family and represents a major viral pathogen in cattle and other ruminants. Infection with BVDV can result in a wide assortment of disease manifestations including resorption, mummification, or abortion of the dead fetus. Recently the point mutation I261M on the thumb domain was shown to confer resistance to BDVD against 227G and other benzimidazole compounds. Here we investigated the role of this mutation by using a multidisciplinary protocol, not involving free energy calculations on structures of the mutated complex which are taken a priori similar to those of the wild one. Namely, we firstly performed MD simulations on the wild and mutated BVDV RdRp proteins in aqueous solution. Then, we selected representative equilibrium conformations by performing a cluster analysis, and ran docking calculations of 277G on representative of the 5 most populated clusters of each protein. Finally, we performed MD simulation on selected complexes as to assess structural and dynamical differences between wild and mutated 227G-protein adducts. Interestingly, the mutation affects the structure and the dynamics of the protein, particularly in the region of binding of the ligand, and this results in a different binding site of 227G with respect to the wild protein. Moreover, while 227G closes the entrance to the RNA strand in the case of the wild protein, a gate and a channel leading to the catalytic site are still present in the mutated complex. These results could offer a possible molecular explanation of the resistance mechanism by mutation I261M

Molecular Rationale behind the Differential Substrate Specificity of Bacterial RND Multi-Drug Transporters

Resistance-Nodulation-cell Division (RND) transporters AcrB and AcrD of Escherichia coli expel a wide range of substrates out of the cell in conjunction with AcrA and TolC, contributing to the onset of bacterial multidrug resistance. Despite sharing an overall sequence identity of ~66% (similarity ~80%), these RND transporters feature distinct substrate specificity patterns whose underlying basis remains elusive. We performed exhaustive comparative analyses of the putative substrate binding pockets considering crystal structures, homology models and conformations extracted from multi-copy μs-long molecular dynamics simulations of both AcrB and AcrD. The impact of physicochemical and topographical properties (volume, shape, lipophilicity, electrostatic potential, hydration and distribution of multi-functional sites) within the pockets on their substrate specificities was quantitatively assessed. Differences in the lipophilic and electrostatic potentials among the pockets were identified. In particular, the deep pocket of AcrB showed the largest lipophilicity convincingly pointing out its possible role as a lipophilicity-based selectivity filter. Furthermore, we identified dynamic features (not inferable from sequence analysis or static structures) such as different flexibilities of specific protein loops that could potentially influence the substrate recognition and transport profile. Our findings can be valuable for drawing structure (dynamics)-activity relationship to be employed in drug design