1,721,114 research outputs found
Simulating transport properties through bacterial channels
No full textGram-negative bacteria have several porins in their outer membrane: they act as gates in the exchange of molecules and are also considered the main pathway for antibiotics. Bacteria are able to resist the action of antibiotics simply by closing off physical access to their interior, either underexpressing porins or decreasing the porin's internal size. The dissemination of pathogens resistant to common antibiotics requires the development of new classes of drugs with improved properties. Understanding how compounds diffuse through bacterial porins can aid in the design of new antibiotics with better penetration power, partially solving one of the main problem of resistance. The diffusion of antibiotics through porins is a molecular-based process, controlled mainly by electrostatic interactions, as has been shown experimentally. Data from single molecule experiments are available in the literature but provide only indirect evidence of the transport. Molecular dynamics simulations at the molecular scale, combined with a recent algorithm able to extend simulations to biologically interesting times, have been shown to complement experiments, providing detailed information on the transport of antibiotics through porins
Physical Insights into Permeation of and Resistance to Antibiotics in Bacteria
No full textBacteria can resist antibiotics simply by hindering physical access to the interior, where in general antibiotic targets are located. Gram-negative bacteria, protected by the outer membrane, possess in the latter several porins that act as a gate for the exchange of small hydrophilic molecules. These porins are water-filled membrane-protein channels that are considered to be the main pathway for different class of antibiotics, such as beta-lactams and fluoroquinolones. Bacte- rial strains resistant to antibiotics can either decrease the density of porins expressed in the outer membrane or decrease the porin internal size by mutating a few amino acids. In both cases, understanding how antibiotics diffuse through bacte- rial porins can help the design of new antibiotics that have better penetrating power. A considerable contribution can be offered by molecular dynamics simulations since reliability of force fields, computer power, and algorithms have consid- erably increased the predictive power thereof. Large systems, as pores inserted in a membrane, and long simulation runs are now feasible, and the time scale can be even extended via the use of accelerated techniques, such as metadynamics, and combined strategies. The details of interactions and processes, extracted from the simulations, complement experi- mental findings and also deepen aspects not accessible to experiments. In this paper we will review the results obtained by our group on this topic with a particular focus on possible general criteria that can guide the rational design of new anti- bacterial compounds
SIMULATION AND MODELING OF THE RHODOBACTER SPHAEROIDES BACTERIAL REACTION CENTER: primary charge separation
No full textThis paper is focused on the molecular dynamics modeling of the primary charge separation in the photosynthetic reaction center (RC) of Rhodobacter sphaeroides. The kinetic parameters for the electron transfer along the active (L) and inactive (M) sides were obtained from a long MD trajectory, 3.4 ns, of the RC in an amphophilic environment made of detergent and water. Both nuclear and electronic polarizations are explicitly included in our calculation. With no postprocessing parameter fit, our modeling computes, for two different charge distributions, the driving forces for the transfer of an excess electron to BL and HL from P*, in good agreement with experiments. The multiexponential kinetics of the primary charge separation is also predicted, consistent with experimentally observed kinetics. The decay of the P* state is composed of four characteristic times due to both the conformational heterogeneity of the protein and the two possible mechanisms, superexchange and sequential. At room temperature, the latter is favored over superexchange with decay rates close to experimental rates. Nevertheless, the proximity between the computed diabatic free-energy surfaces on the L side yields a superexchange electronic coupling matrix element very near its resonance point and, thus, very sensitive to changes in the driving forces. For variations of at most 1.3 kcal mol-1, smaller than the accuracy of our theoretical approach, superexchange might be favored over the two- step mechanism. Finally, our molecular modeling strongly indicates that the position of the diabatic free- energy surfaces for the primary charge separation cannot by itself account for the directionality of the primary charge separation. A strong electrostatic potential around the special pair that favors the polarization of the transferring electron toward regions closer to BL than to BM is found. This polarization could significantly increase the electronic coupling between P* and BL, thus accounting, at least in part, for the directionality of the electron transfer
molecular dynamics simulation of POPC at low hydration near the liquid crystal phase transition
No full textWe report results of a preliminary molecular dynamics study of a 1-palmitoyl-2-oleoylphosphatidyicholine (POPC) bilayer at low hydration (5% in weight). Our results suggest a gel phase structure where the oleic chain is bent recalling the crystalline oleic acid structure. We have also found a discontinuity in the volume/temperature curve which might be related to the gel to liquid crystal phase transition in POP
Physical methods to quantify small antibiotic molecules uptake into Gram-negative bacteria
No full textThe development of antibiotics against Gram-negative bacteria is a challenge: any active compound must cross the outer cell envelope composed of a hydrophilic highly charged lipopolysaccharide layer followed by a tight hydrophobic layer containing water filled gates called porins to reach the hydrophilic periplasmic space and depending on the target with the further need to cross the hydrophobic inner membrane. In addition to a possible rapid enzymatic deactivation efflux pumps shuffle compounds back outside. The resulting low permeability of cell envelope requires high dose and leads therefore to toxicity problems. Despite its relevance the permeability barrier in Gram-negative bacteria is not well understood partially caused by the lack of appropriate direct assays. Here we give a brief introduction on current available techniques to quantify passive diffusion of small hydrophilic molecules into Gram-negative bacteri
Simulation and modeling of the rhodobacter sphaeroides bacterial reaction center: structure and interaction
No full textIn this paper, we present the structural and dynamic results of a 3.4 ns molecular dynamics simulation of a reaction center protein immersed in a micelle-like environment formed by a detergent, lauryl dimethyl amino oxide or LDAO, and hydrated by more than 6000 additional water molecules. The whole system, ≈40 000 atoms, was simulated using an all-atom force field with refined potential parameters developed by us to describe the protein cofactors and the detergent molecules. LDAO, inserted at the beginning of the run in a configuration far from equilibrium, rearranged forming a micelle attached to the hydrophobic regions of the protein. The micelle is a stable and dynamic structure over the whole trajectory and prevents the protein and the internal cofactors from contacts with water. Comparing our simulated system with the high-resolution crystallographic structure, the deviations of the backbone atoms are small, less than 1.8 Å after 3.4 ns, and the chromophore arrangement geometry is stable and close to X-ray for the whole simulation. Thus, our system constitutes a realistic model to investigate at an atomic level the role of the protein environment on the charge transfer processes taking place in this complex. Related to the functionality of this RC protein, we observe the isomerization of the tyr M210 which is directly coupled with the primary electron transfer. Concerning the branch functionality of the RC, we observe that the computed minimum distance between the chromophores on the L and M side has a different dynamic behavior and is smaller on average for transitions on the L side. This finding might have some bearing on the electron-transfer asymmetry of the primary charge transfer
Transport of Antibiotics through the Substrate Specific OprD Channel of Pseudomonas Aeruginosa
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