Brownian dynamics simulations of protein folding: Access to milliseconds time scale and beyond

Protein folding occurs on a time scale ranging from milliseconds to minutes for a majority of proteins. Computer simulation of protein folding, from a random configuration to the native structure, is nontrivial owing to the large disparity between the simulation and folding time scales. As an effort to overcome this limitation, simple models with idealized protein subdomains, e.g., the diffusion–collision model of Karplus and Weaver, have gained some popularity. We present here new results for the folding of a four-helix bundle within the framework of the diffusion–collision model. Even with such simplifying assumptions, a direct application of standard Brownian dynamics methods would consume 10,000 processor-years on current supercomputers. We circumvent this difficulty by invoking a special Brownian dynamics simulation. The method features the calculation of the mean passage time of an event from the flux overpopulation method and the sampling of events that lead to productive collisions even if their probability is extremely small (because of large free-energy barriers that separate them from the higher probability events). Using these developments, we demonstrate that a coarse-grained model of the four-helix bundle can be simulated in several days on current supercomputers. Furthermore, such simulations yield folding times that are in the range of time scales observed in experiments.

Coalescent estimates of HIV-1 generation time in vivo

The generation time of HIV Type 1 (HIV-1) in vivo has previously been estimated using a mathematical model of viral dynamics and was found to be on the order of one to two days per generation. Here, we describe a new method based on coalescence theory that allows the estimate of generation times to be derived by using nucleotide sequence data and a reconstructed genealogy of sequences obtained over time. The method is applied to sequences obtained from a long-term nonprogressing individual at five sampling occasions. The estimate of viral generation time using the coalescent method is 1.2 days per generation and is close to that obtained by mathematical modeling (1.8 days per generation), thus strengthening confidence in estimates of a short viral generation time. Apart from the estimation of relevant parameters relating to viral dynamics, coalescent modeling also allows us to simulate the evolutionary behavior of samples of sequences obtained over time.

Effects of sampling standardization on estimates of Phanerozoic marine diversification

Global diversity curves reflect more than just the number of taxa that have existed through time: they also mirror variation in the nature of the fossil record and the way the record is reported. These sampling effects are best quantified by assembling and analyzing large numbers of locality-specific biotic inventories. Here, we introduce a new database of this kind for the Phanerozoic fossil record of marine invertebrates. We apply four substantially distinct analytical methods that estimate taxonomic diversity by quantifying and correcting for variation through time in the number and nature of inventories. Variation introduced by the use of two dramatically different counting protocols also is explored. We present sampling-standardized diversity estimates for two long intervals that sum to 300 Myr (Middle Ordovician-Carboniferous; Late Jurassic-Paleogene). Our new curves differ considerably from traditional, synoptic curves. For example, some of them imply unexpectedly low late Cretaceous and early Tertiary diversity levels. However, such factors as the current emphasis in the database on North America and Europe still obscure our view of the global history of marine biodiversity. These limitations will be addressed as the database and methods are refined.

A general additive distance with time-reversibility and rate variation among nucleotide sites.

As additivity is a very useful property for a distance measure, a general additive distance is proposed under the stationary time-reversible (SR) model of nucleotide substitution or, more generally, under the stationary, time-reversible, and rate variable (SRV) model, which allows rate variation among nucleotide sites. A method for estimating the mean distance and the sampling variance is developed. In addition, a method is developed for estimating the variance-covariance matrix of distances, which is useful for the statistical test of phylogenies and molecular clocks. Computer simulation shows (i) if the sequences are longer than, say, 1000 bp, the SR method is preferable to simpler methods; (ii) the SR method is robust against deviations from time-reversibility; (iii) when the rate varies among sites, the SRV method is much better than the SR method because the distance is seriously underestimated by the SR method; and (iv) our method for estimating the sampling variance is accurate for sequences longer than 500 bp. Finally, a test is constructed for testing whether DNA evolution follows a general Markovian model.

A sampling problem in molecular dynamics simulations of macromolecules.

Correlations in low-frequency atomic displacements predicted by molecular dynamics simulations on the order of 1 ns are undersampled for the time scales currently accessible by the technique. This is shown with three different representations of the fluctuations in a macromolecule: the reciprocal space of crystallography using diffuse x-ray scattering data, real three-dimensional Cartesian space using covariance matrices of the atomic displacements, and the 3N-dimensional configuration space of the protein using dimensionally reduced projections to visualize the extent to which phase space is sampled.

Estimation of Time-Limited Channel Spectra From Nonuniform Samples

This paper deals with the estimation of a time-invariant channel spectrum from its own nonuniform samples, assuming there is a bound on the channel’s delay spread. Except for this last assumption, this is the basic estimation problem in systems providing channel spectral samples. However, as shown in the paper, the delay spread bound leads us to view the spectrum as a band-limited signal, rather than the Fourier transform of a tapped delay line (TDL). Using this alternative model, a linear estimator is presented that approximately minimizes the expected root-mean-square (RMS) error for a deterministic channel. Its main advantage over the TDL is that it takes into account the spectrum’s smoothness (time width), thus providing a performance improvement. The proposed estimator is compared numerically with the maximum likelihood (ML) estimator based on a TDL model in pilot-assisted channel estimation (PACE) for OFDM.

Evaluation of sampling method effects in 3D non-rigid registration

Since the beginning of 3D computer vision problems, the use of techniques to reduce the data to make it treatable preserving the important aspects of the scene has been necessary. Currently, with the new low-cost RGB-D sensors, which provide a stream of color and 3D data of approximately 30 frames per second, this is getting more relevance. Many applications make use of these sensors and need a preprocessing to downsample the data in order to either reduce the processing time or improve the data (e.g., reducing noise or enhancing the important features). In this paper, we present a comparison of different downsampling techniques which are based on different principles. Concretely, five different downsampling methods are included: a bilinear-based method, a normal-based, a color-based, a combination of the normal and color-based samplings, and a growing neural gas (GNG)-based approach. For the comparison, two different models have been used acquired with the Blensor software. Moreover, to evaluate the effect of the downsampling in a real application, a 3D non-rigid registration is performed with the data sampled. From the experimentation we can conclude that depending on the purpose of the application some kernels of the sampling methods can improve drastically the results. Bilinear- and GNG-based methods provide homogeneous point clouds, but color-based and normal-based provide datasets with higher density of points in areas with specific features. In the non-rigid application, if a color-based sampled point cloud is used, it is possible to properly register two datasets for cases where intensity data are relevant in the model and outperform the results if only a homogeneous sampling is used.

Concentrations of perfluorinated carboxylic acids (PFCAs) and sulfonic acids (PFSAs) in liver samples of different marine mammals (1984-2009)

Temporal variations in concentrations of perfluorinated carboxylic acids (PFCAs) and sulfonic acids (PFSAs), including perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) structural isomers, were examined in livers of pilot whale (Globicephala melas), ringed seal (Phoca hispida), minke whale (Balaenoptera acutorostrata), harbor porpoise (Phocoena phocoena), hooded seal (Cystophora cristata), Atlantic white-sided dolphin (Lagenorhynchus acutus) and in muscle tissue of fin whales (Balaenoptera physalus). The sampling spanned over 20 years (1984-2009) and covered a large geographical area of the North Atlantic and West Greenland. Liver and muscle samples were homogenized, extracted with acetonitrile, cleaned up using hexane and solid phase extraction (SPE), and analyzed by liquid chromatography with negative electrospray tandem mass spectrometry (LC-MS/MS). In general, the levels of the long-chained PFCAs (C9-C12) increased whereas the levels of PFOS remained steady over the studied period. The PFOS isomer pattern in pilot whale liver was relatively constant over the sampling years. However, in ringed seals there seemed to be a decrease in linear PFOS (L-PFOS) with time, going from 91% in 1984 to 83% in 2006.

(Table S1) Boron isotope and trace element data and reconstructed carbonate system parameters, ODP Holes 122-761B and 154-926A

The middle Miocene Climatic Optimum (17-15 Ma; MCO) is a period of global warmth and relatively high CO2 and is thought to be associated with a significant retreat of the Antarctic Ice Sheet (AIS). We present here a new planktic foraminiferal d11B record from 16.6 to 11.8 Ma from two deep ocean sites currently in equilibrium with the atmosphere with respect to CO2. These new data demonstrate that the evolution of global climate during the middle Miocene (as reflected by changes in the cyrosphere) was well correlated to variations in the concentration of atmospheric CO2. What is more, within our sampling resolution (~1 sample per 300 kyr) there is no evidence of hysteresis in the response of ice volume to CO2 forcing during the middle Miocene, contrary to what is understood about the Antarctic Ice Sheet from ice sheet modelling studies. In agreement with previous data, we show that absolute levels of CO2 during the MCO were relatively modest (350-400 ppm) and levels either side of the MCO are similar or lower than the pre-industrial (200-260 ppm). These new data imply the presence of either a very dynamic AIS at relatively low CO2 during the middle Miocene or the advance and retreat of significant northern hemisphere ice. Recent drilling on the Antarctic margin and shore based studies indicate significant retreat and advance beyond the modern limits of the AIS did occur during the middle Miocene, but the complete loss of the AIS was unlikely. Consequently, it seems that ice volume and climate variations during the middle Miocene probably involved a more dynamic AIS than the modern but also some component of land-based ice in the northern hemisphere.

Paleontological and sedimentological investigations of a sediment profile from northeast Greenland

The Kap Mackenzie area on the outer coast of northeast Greenland was glaciated during the last glacial stage, and pre-Holocene shell material was brought to the area. Dating of marine shells indicates that deglaciation occurred in the earliest Holocene, before 10 800 cal. a BP. The marine limit is around 53 m a.s.l. In the wake of the deglaciation, a glaciomarine fauna characterized the area, but after c. one millennium a more species-rich marine fauna took over. This fauna included Mytilus edulis and Mysella sovaliki, which do not live in the region at present; the latter is new to the Holocene fauna of northeast Greenland. The oldest M. edulis sample is dated to c. 9500 cal. a BP, which is the earliest date for the species from the region and indicates that the Holocene thermal maximum began earlier in the region than previously documented. This is supported by driftwood dated to c. 9650 cal. a BP, which is the earliest driftwood date so far from northeastern Greenland and implies that the coastal area was at least partly free of sea ice in summer. As indicated by former studies, the Storegga tsunami hit the Kap Mackenzie area at c. 8100 cal. a BP. Loon Lake, at 18 m a.s.l., was isolated from the sea at c. 6200 cal. a BP, which is distinctly later than expected from existing relative sea-level curves for the region.

Planktonic foraminifera of sediment trap samples

Biweekly sediment trap samples and concurrent hydrographic measurements collected between March 2005 and October 2008 from the Cariaco Basin, Venezuela, are used to assess the relationship between [CO3]2- and the area densities (ho A) of two species of planktonic foraminifera (Globigerinoides ruber (pink) and Globigerinoides sacculifer). Calcification temperatures were calculated for each sample using species-appropriate oxygen isotope (d18O) temperature equations that were then compared to monthly temperature profiles taken at the study site in order to determine calcification depth. Ambient [CO3]2- was determined for these calcification depths using alkalinity, pH, temperature, salinity, and nutrient concentration measurements taken during monthly hydrographic cruises. The rho A, which is representative of calcification efficiency, is determined by dividing individual foraminiferal shell weights (±0.43 µg) by their associated silhouette areas and taking the sample average. The results of this study show a strong correlation between rho A and ambient [CO3]2- for both G. ruber and G. sacculifer (R**2 = 0.89 and 0.86, respectively), confirming that [CO3]2- has a pronounced effect on the calcification of these species. Though the rho A for both species reveal a highly significant (p < 0.001) relationship with ambient [CO3]2-, linear regression reveals that the extent to which [CO3]2- influences foraminiferal calcification is species specific. Hierarchical regression analyses indicate that other environmental parameters (temperature and [PO4]3-) do not confound the use of G. ruber and G. sacculifer rho A as a predictor for [CO3]2-. This study suggests that G. ruber and G. sacculifer rho A can be used as reliable proxies for past surface ocean [CO3]2?-

Sediment and organic matter properties, and molecular formula from sampling locations in the Northern Black Sea

Remineralization of organic matter in reactive marine sediments releases nutrients and dissolved organic matter (DOM) into the ocean. Here we focused on the molecular-level characterization of DOM by high-resolution Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) in sediment pore waters and bottom waters from contrasting redox regimes in the northern Black Sea with particular emphasis on nitrogen-bearing compounds to derive an improved understanding of the molecular transformations involved in nitrogen release. The number of nitrogen-bearing molecules is generally higher in pore waters than in bottom waters. This suggests intensified degradation of nitrogen-bearing precursor molecules such as proteins in anoxic sediments: No significant difference was observed between sediments deposited under oxic vs anoxic conditions (average O/C ratios of 0.55) suggesting that the different organic matter quality induced by contrasting redox conditions does not impact protein diagenesis in the subseafloor. Compounds in the pore waters were on average larger, less oxygenated, and had a higher number of unsaturations. Applying a mathematical model, we could show that the assemblages of nitrogen-bearing molecular formulas are potential products of proteinaceous material that was transformed by the following reactions: (a) hydrolysis and deamination, both reducing the molecular size and nitrogen content of the products and intermediates; (b) oxidation and hydration of the intermediates; and (c) methylation and dehydration.

Sedimentology at the continental margin of the southern Weddell Sea

During four expeditions with RV "Polarstern" at the continental margin of the southern Weddell Sea, profiling and geological sampling were carried out. A detailed bathymetric map was constructed from echo-sounding data. Sub-bottom profiles, classified into nine echotypes, have been mapped and interpreted. Sedimentological analyses were carried out on 32 undisturbed box grab surface samples, as well as on sediment cores from 9 sites. Apart from the description of the sediments and the investigation of sedimentary structures on X-radiographs the following characteristics were determined: grain-size distributions; carbonate and Corg content; component distibutions in different grain-size fractions; stable oxygen and carbon isotopes in planktic and, partly, in benthic foraminifers; and physical properties. The stratigraphy is based On 14C-dating, oxygen isotope Stages and, at one site, On paleomagnetic measurements and 230Th-analyses The sediments represent the period of deposition from the last glacial maximum until recent time. They are composed predominantly of terrigenous components. The formation of the sediments was controlled by glaciological, hydrographical and gravitational processes. Variations in the sea-ice coverage influenced biogenic production. The ice sheet and icebergs were important media for sediment transport; their grounding caused compaction and erosion of glacial marine sediments on the outer continental shelf. The circulation and the physical and chemical properties of the water masses controlled the transport of fine-grained material, biogenic production and its preservation. Gravitational transport processes were the inain mode of sediment movements on the continental slope. The continental ice sheet advanced to the shelf edge and grounded On the sea-floor, presumably later than 31,000 y.B.P. This ice movement was linked with erosion of shelf sediments and a very high sediment supply to the upper continental slope from the adiacent southern shelf. The erosional surface On the shelf is documented in the sub-bottom profiles as a regular, acoustically hard reflector. Dense sea-ice coverage above the lower and middle continental slope resulted in the almost total breakdown of biogenic production. Immediately in front of the ice sheet, above the upper continental slope, a <50 km broad coastal polynya existed at least periodically. Biogenic production was much higher in this polynya than elsewhere. Intense sea-ice formation in the polynya probably led to the development of a high salinity and, consequently, dense water mass, which flowed as a stream near bottom across the continental slope into the deep sea, possibly contributing to bottom water formation. The current velocities of this water mass presumably had seasonal variations. The near-bottom flow of the dense water mass, in combination with the gravity transport processes that arose from the high rates of sediment accumulation, probably led to erosion that progressed laterally from east to West along a SW to NE-trending, 200 to 400 m high morphological step at the continental slope. During the period 14,000 to 13,000 y.B.P., during the postglacial temperature and sea-level rise, intense changes in the environmental conditions occured. Primarily, the ice masses on the outer continental shelf started to float. Intense calving processes resulted in a rapid retreat of the ice edge to the south. A consequence of this retreat was, that the source area of the ice-rafted debris changed from the adjacent southern shelf to the eastern Weddell Sea. As the ice retreated, the gravitational transport processes On the continental slope ceased. Soon after the beginning of the ice retreat, the sea-ice coverage in the whole research area decreased. Simultaneously, the formation of the high salinity dense bottom water ceased, and the sediment composition at the continental slope then became influenced by the water masses of the Weddell Gyre. The formation of very cold Ice Shelf Water (ISW) started beneath the southward retreating Filchner-Ronne Ice Shelf somewhat later than 12,000 y.B.P. The ISW streamed primarily with lower velocities than those of today across the continental slope, and was conducted along the erosional step on the slope into the deep sea. At 7,500 y.B.P., the grounding line of the ice masses had retreated > 400 km to the south. A progressive retreat by additional 200 to 300 km probably led to the development of an Open water column beneath the ice south of Berkner Island at about 4,000 y.B.P. This in turn may have led to an additional ISW, which had formed beneath the Ronne Ice Shelf, to flow towards the Filcher Ice Shelf. As a result, increased flow of ISW took place over the continental margin, possibly enabling the ISW to spill over the erosional step On the upper continental slope towards the West. Since that time, there is no longer any documentation of the ISW in the sedimentary Parameters on the lower continental slope. There, recent sediments reflect the lower water masses of the Weddell Gyre. The sea-ice coverage in early Holocene time was again so dense that biogenic production was significantly restricted.

(Table 1) Age of sediments with anomalously high Hg concentrations in core BDP-98, Lake Baikal

Mercury distribution was examined in the sediments of Lake Baikal that were sampled within the scope of the Baikal Drilling International Project in 1996-1999. The Hg concentrations in the ancient sediments are close to those in the modern sediments with the exception of a few peak values, whose ages coincide with those of active volcanism in adjacent areas. Mercury was demonstrated to be contained in the sediments in the adsorbed Hg0 mode, predominantly in relation with organic matter. When the organic matter of the bottom sediments is decomposed in the course of lithification, Hg is retained in the sediments adsorbed on the residual organic matter, and the concentration of this element corresponds to its initial content in the bottom sediments during their accumulation. Mercury concentrations in lithologically distinct bottom sediments of Lake Baikal and its sediments as a whole depend on the climate. Sediments that were formed during warm periods of time contain more Hg than those produced during cold periods or glaciation. Periodical variations in the Hg concentrations in the bottom sediments of Lake Baikal reflect the variations in the contents of this element in the Earth's atmosphere in the Late Cenozoic, which were, in turn, controlled by the climatic variations on the planet and, thus, can be used for detailed reconstructions of variations in the average global temperature near the planet's surface.