Structural dynamics of the mitochondrial ADP/ATP carrier revealed by molecular dynamics simulation studies

The mitochondrial adenosine diphosphate/adenosine triphosphate (ADP/ATP) carrier has been recently crystallized in complex with its specific inhibitor carboxyatractyloside (CATR). In the crystal structure, the six-transmembrane helix bundle that defines the nucleotide translocation pathway is closed on the matrix side due to sharp kinks in the odd-numbered helices. The closed conformation is further sealed by the loops protruding into the matrix that interact through an intricate network of charge-pairs. To gain insight into its structural dynamics we performed molecular dynamics (MD) simulation studies of the ADP/ATP carrier with and without its cocrystallized inhibitor. The two trajectories sampled a conformational space around two different configurations characterized by distinct salt-bridge networks with a significant shift from inter- to intrarepeat bonding on the matrix side in the absence of CATR. Analysis of the geometrical parameters defining the transmembrane helices showed that even-numbered helices can undergo a face rotation, whereas odd-numbered helices can undergo a change in the wobble angle with a conserved proline acting as molecular hinge. Our results provide new information on the dynamical properties of the ADP/ATP carrier and for the first time yield a detailed picture of a stable carrier conformation in absence of the inhibitor.     

Radiation damage in the bulk and at the surface

The UK environmental e-science initiative supports the development and modification of simulation tools used to study radiation damage effects. We discuss the development and modification to the DL_POLY molecular dynamics (MD) code. Using the newly developed tools, we study the effects of radiation damage related to the safe encapsulation of highly radioactive materials, including nuclear waste. We address the possible differences between the radiation damage in the bulk and at the surface of a material, and perform MD simulations of energetic events in zircon structure. We find that in the case of readily amorphizable material, the formation of a stable alternative covalent network reduces the possible effect of the surface on the damaged structure.     

Nonlinear acoustics in pant hoots of common chimpanzees (Pan troglodytes): frequency jumps, subharmonics, biphonation, and deterministic chaos

The pant hoot calls produced by common chimpanzees (Pan troglodytes) are multi-call vocalizations that have figured prominently in investigations of acoustic communication in this species. Although pant hoots are predominantly harmonically structured, they can exhibit an acoustic complexity that has recently been linked to nonlinearity in the vocal-fold dynamics underlying typical mammalian sound production. We examined the occurrence of these sorts of nonlinear phenomena in pant hoot vocalizations, contrasting quieter and lower-pitched "introduction" components with loud and high-pitched "climax" calls in the same bouts. Spectrographic evidence revealed four kinds of nonlinear phenomena, including discrete frequency jumps, subharmonics, biphonation, and deterministic chaos. While these events were virtually never observed during the introduction, they occurred in more than half of the climax calls. Biphonation was by far the most common phenomenon, followed by subharmonics, chaos, and frequency jumps. Individual callers varied in the degree to which their climax calls exhibited nonlinear phenomena, but were consistent in showing more biphonation than other forms. These outcomes show that nonlinear phenomena are routinely present in chimpanzee pant hoots, and help lay the foundation for investigating the function of such events.     

Response of SCP-2L domain of human MFE-2 to ligand removal: binding site closure and burial of peroxisomal targeting signal

In the study of the structure and function relationship of human MFE-2, we have investigated the dynamics of human MFE-2SCP-2L (hSCP-2L) and its response to ligand removal. A comparison was made with homologous rabbit SCP-2. Breathing and a closing motion are found, identifiable with an adjustment in size and a closing off of the binding pocket. Crucial residues for structural integrity have been identified. Particularly mobile areas of the protein are loop 1 that is connecting helices A and C in space, and helix D, next to the entrance of the pocket. In hSCP-2L, the binding pocket gets occupied by Phe93, which is making a tight hydrophobic contact with Trp36. In addition, it is found that the C-terminal peroxisomal targeting signal (PTS1) that is solvent exposed in the complexed structure becomes buried when no ligand is present. Moreover, an anti-correlation exists between burial of PTS1 and the size of the binding pocket. The results are in accordance with plant nsLTPs, where a similar accommodation of binding pocket size was found after ligand binding/removal. Furthermore, the calculations support the suggestion of a ligand-assisted targeting mechanism.     

An alternate sucrose binding mode in the E203Q Arabidopsis invertase mutant: an X-ray crystallography and docking study

In the present study, we report on the X-ray crystallographic structure of a GH32 invertase mutant, (i.e., the Arabidopsis thaliana cell-wall invertase 1-E203Q, AtcwINV1-mutant) in complex with sucrose. This structure was solved to reveal the features of sugar binding in the catalytic pocket. However, as demonstrated by the X-ray structure the sugar binding and the catalytic pocket arrangement is significantly altered as compared with what was expected based on previous X-ray structures on GH-J clan enzymes. We performed a series of docking and molecular dynamics simulations on various derivatives of AtcwINV1 to reveal the reasons behind this modified sugar binding. Our results demonstrate that the E203Q mutation introduced into the catalytic pocket triggers conformational changes that alter the wild type substrate binding. In addition, this study also reveals the putative productive sucrose binding modus in the wild type enzyme.     

Simulating transmission and control of Taenia solium infections using a Reed-Frost stochastic model

The transmission dynamics of the human-pig zoonotic cestode Taenia solium are explored with both deterministic and stochastic versions of a modified Reed-Frost model. This model, originally developed for microparasitic infections (i.e. bacteria, viruses and protozoa), assumes that random contacts occur between hosts and that hosts can be either susceptible, infected or 'recovered and presumed immune'. Transmission between humans and pigs is modelled as susceptible roaming pigs scavenging on human faeces infected with T. solium eggs. Transmission from pigs to humans is modelled as susceptible humans eating under-cooked pork meat harbouring T. solium metacestodes. Deterministic models of each scenario were first run, followed by stochastic versions of the models to assess the likelihood of infection elimination in the small population modelled. The effects of three groups of interventions were investigated using the model: (i) interventions affecting the transmission parameters such as use of latrines, meat inspection, and cooking habits; (ii) routine interventions including rapid detection and treatment of human carriers or pig vaccination; and (iii) treatment interventions of either humans or pigs. It is concluded that mass-treatment can result in a short term dramatic reduction in prevalence, whereas interventions targeting interruption of the life cycle lead to long-term reduction in prevalence.     

Putative local adaptations modulate the interactions of the carnivorous plant Drosera uniflora Willd (1809) (Droseraceae) with cushion and shrub nurse plants

Cushion and shrub plants are typical high mountain nurse plants. In Magellanic tundras of the Cordillera del Sarao on the coast of Chile, the carnivorous plant Drosera uniflora grows in association with cushions of Donatia fascicularis and the shrubs Chusquea montana var. nigricans and Lepidothamnus fonkii. The different microhabitats for recruitment, in addition to the limited gene flow of D. uniflora, enable us to hypothesise that this plant manifests putative local adaptations, expressed in seed germination and population abundance. Our aim was to evaluate the local adaptation of D. uniflora to cushion and shrub microhabitats by estimating germination and abundance. Local adaptation of seed germination was determined by means of reciprocal transplant experiments. Abundance was determined in small plots located inside, on the edge and outside the nurse plants. Seed origin and growth substrate play a decisive role in D. uniflora germination. Seeds that originate from cushions plant habitat and germinate in the same substrate do so in greater numbers than when those which originate from shrubby habitats. Conversely, seeds that originate from shrubby habitat and germinate in the same substrate do not exhibit significant differences. Abundance was always greater inside than outside of the nurse plants. We concluded that availability and quality of different microhabitats for seed germination and recruitment, together with a limited gene flow, would trigger putative local adaptations in D. uniflora, modulating a long history of interactions with the plants that act as nurse plants.     

Inter-chromosomal Contact Properties in Live-Cell Imaging and in Hi-C

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Protein molecular dynamics with electrostatic force entirely determined by a single Poisson-Boltzmann calculation

The electrostatic force including the intramolecular Coulombic interactions and the electrostatic contribution of solvation effect were entirely calculated by using the finite difference Poisson-Boltzmann method (FDPB), which was incorporated into the GROMOS96 force field to complete a new finite difference stochastic dynamics procedure (FDSD). Simulations were performed on an insulin dimer. Different relative dielectric constants were successively assigned to the protein interior; a value of 17 was selected as optimal for our system. The simulation data were analyzed and compared with those obtained from 500-ps molecular dynamics (MD) simulation with explicit water and a 500-ps conventional stochastic dynamics (SD) simulation without the mean solvent force. The results indicate that the FDSD method with GROMOS96 force field is suitable to study the dynamics and structure of proteins in solution if used with the optimal protein dielectric constant.     

Remote homolog detection using local sequence-structure correlations

Remote homology detection refers to the detection of structural homology in proteins when there is little or no sequence similarity. In this article, we present a remote homolog detection method called SVM-HMMSTR that overcomes the reliance on detectable sequence similarity by transforming the sequences into strings of hidden Markov states that represent local folding motif patterns. These state strings are transformed into fixed-dimension feature vectors for input to a support vector machine. Two sets of features are defined: an order-independent feature set that captures the amino acid and local structure composition; and an order-dependent feature set that captures the sequential ordering of the local structures. Tests using the Structural Classification of Proteins (SCOP) 1.53 data set show that the SVM-HMMSTR gives a significant improvement over several current methods.