40 research outputs found
Free energy prediction of biomolecular systems using ensembles of structures
Knowledge about the underlying free energy landscape of biomolecules is crucial for a basic understanding of the inner workings of proteins. Its fast and accurate calculation is indispensable for conformational analysis, structure-based protein design or for protein docking. On the one hand, existing rigorous methods like free energy perturbation or thermodynamic integration are time-consuming and cannot be used for large scans required for protein or vaccine design. On the other hand, fast treatments rely on empirical or statistical data and deliberately neglect protein flexibility and are therefore limited in accuracy.
In this thesis, a novel method for the estimation of free energy changes upon mutation is proposed combining a physical effective energy function with an efficient sampling of available conformational space. The energy function is based on physical chemistry and an efficient continuum solvent approach. It is averaged over alternative protein conformations fulfilling geometric constraints. The main advantage of our method is its inclusion of full protein flexibility, which dramatically improves the prediction quality for protein-protein binding affinities. Due to its hundredfold gain in speed with respect to conventional methods the method enables e.g. full mutant scanning of protein-protein interfaces.
The method was successfully applied to the study of mutational effects on protein-protein and protein-peptide binding.Die Kenntnis der Freie-Energielandschaft von Proteinen ist essentiell fĂŒr ein tiefergehendes VerstĂ€ndnis ihrer Funktionsweise. Die schnelle und prĂ€zise Bestimmung der Freien Energie ist wichtig fĂŒr strukturbasierte Analysen, Proteindesign oder fĂŒr das Proteindocking. Methoden wie die Freie Energie Störungsrechnung liefern physikalisch korrekte Beschreibungen, die allerdings mit hohem Rechenaufwand verbunden sind und daher fĂŒr umfĂ€ngliche Untersuchungen ungeeignet sind. Schnelle Methoden stĂŒtzen sich dagegen auf empirische oder statistische Daten, vernachlĂ€ssigen dabei die ProteinflexibilitĂ€t und weisen daher eine eingeschrĂ€nkte Genauigkeit auf.
Diese Arbeit stellt eine neu entwickelte Methode zur Berechnung von Freien EnergieĂ€nderungen durch Mutationen vor, die eine physikalisch effektive Energiefunktion mit einer effizienten Abtastung des verfĂŒgbaren Konformationsraumes kombiniert.
Die ĂŒber alternative Proteinstrukturen gemittelte Energiefunktion basiert auf physikalischer Chemie und einer effizienten Behandlung des Lösungsmittels. Der gröĂte Vorteil unserer Methode ist die BerĂŒcksichtigung der vollen FlexibilitĂ€t, welche die VorhersagequalitĂ€t von BindungsaffinitĂ€ten deutlich steigert. Durch einen hundertfachen Geschwindigkeitszuwachs im Vergleich zu konventionellen Methoden werden Studien ermöglicht, die den vollen Mutationsraum von Protein-Protein GrenzflĂ€chen abdecken.
Die Methode wurde erfolgreich angewandt zur Analyse der Protein-Protein sowie der Protein-Peptid Bindung
Fluid evolution in CM carbonaceous chondrites tracked through the oxygen isotopic compositions of carbonates
The oxygen isotopic compositions of calcite grains in four CM carbonaceous chondrites have been determined by NanoSIMS, and results reveal that aqueous solutions evolved in a similar manner between parent body regions with different intensities of aqueous alteration. Two types of calcite were identified in Murchison, Mighei, Cold Bokkeveld and LaPaz Icefield 031166 by differences in their petrographic properties and oxygen isotope values. Type 1 calcite occurs as small equant grains that formed by filling of pore spaces in meteorite matrices during the earliest stages of alteration. On average, the type 1 grains have a ÎŽ18O of âŒ32â36â° (VSMOW), and Î17O of between âŒ2â° and â1â°. Most grains of type 2 calcite precipitated after type 1. They contain micropores and inclusions, and have replaced ferromagnesian silicate minerals. Type 2 calcite has an average ÎŽ18O of âŒ21â24â° (VSMOW) and a Î17O of between âŒâ1â° and â3â°. Such consistent isotopic differences between the two calcite types show that they formed in discrete episodes and from solutions whose ÎŽ18O and ÎŽ17O values had changed by reaction with parent body silicates, as predicted by the closed-system model for aqueous alteration. Temperatures are likely to have increased over the timespan of calcite precipitation, possibly owing to exothermic serpentinisation. The most highly altered CM chondrites commonly contain dolomite in addition to calcite. Dolomite grains in two previously studied CM chondrites have a narrow range in ÎŽ18O (âŒ25â29â° VSMOW), with Î17O âŒâ1â° to â3â°. These grains are likely to have precipitated between types 1 and 2 calcite, and in response to a transient heating event and/or a brief increase in fluid magnesium/calcium ratios. In spite of this evidence for localised excursions in temperature and/or solution chemistry, the carbonate oxygen isotope record shows that fluid evolution was comparable between many parent body regions. The CM carbonaceous chondrites studied here therefore sample either several parent bodies with a very similar initial composition and evolution or, more probably, a single C-type asteroid
Melting and differentiation of early-formed asteroids: The perspective from high precision oxygen isotope studies
A number of distinct methodologies are available for determining the oxygen isotope composition of minerals and rocks, these include laser-assisted fluorination, secondary ion mass spectrometry (SIMS)and UV laser ablation. In this review we focus on laser-assisted fluorination, which currently achieves the highest levels of precision available for oxygen isotope analysis. In particular, we examine how results using this method have furthered our understanding of early-formed differentiated meteorites. Due to its rapid reaction times and low blank levels, laser-assisted fluorination has now largely superseded the conventional externally-heated Ni âbombâ technique for bulk analysis. Unlike UV laser ablation and SIMS analysis, laser-assisted fluorination is not capable of focused spot analysis. While laser fluorination is now a mature technology, further analytical improvements are possible via refinements to the construction of sample chambers, clean-up lines and the use of ultra-high resolution mass spectrometers.
High-precision oxygen isotope analysis has proved to be a particularly powerful technique for investigating the formation and evolution of early-formed differentiated asteroids and has provided unique insights into the interrelationships between various groups of achondrites. A clear example of this is seenin samples that lie close to the terrestrial fractionation line (TFL). Based on the data from conventional oxygen isotope analysis, it was suggested that the main-group pallasites, the howardite eucrite diogenite suite (HEDs) and mesosiderites could all be derived from a single common parent body. However,high precision analysis demonstrates that main-group pallasites have a Î17O composition that is fully resolvable from that of the HEDs and mesosiderites, indicating the involvement of at least two parent bodies. The range of Î17O values exhibited by an achondrite group provides a useful means of assessing the extent to which their parent body underwent melting and isotopic homogenization. Oxygen isotope analysis can also highlight relationships between ungrouped achondrites and the more well-populated groups. A clear example of this is the proposed link between the evolved GRA 06128/9 meteorites and the brachinites.
The evidence from oxygen isotopes, in conjunction with that from other techniques, indicates that we have samples from approximately 110 asteroidal parent bodies (âŒ60 irons, âŒ35 achondrites and stony-iron, and âŒ15 chondrites) in our global meteorite collection. However, compared to the likely size of the original protoplanetary asteroid population, this is an extremely low value. In addition, almost all of the differentiated samples (achondrites, stony-iron and irons) are derived from parent bodies that were highly disrupted early in their evolution.
High-precision oxygen isotope analysis of achondrites provides some important insights into the origin of mass-independent variation in the early Solar System. In particular, the evidence from various primitive achondrite groups indicates that both the slope 1 (Y&R) and CCAM lines are of primordial significance. Î17O differences between water ice and silicate-rich solids were probably the initial source of the slope 1 anomaly. These phases most likely acquired their isotopic composition as a result of UV photo-dissociation of CO that took place either in the early solar nebula or precursor giant molecular cloud. Such small-scale isotopic heterogeneities were propagated into larger-sized bodies, such as asteroids and planets, as a result of early Solar System processes, including dehydration, aqueous alteration,melting and collisional interactions
Type 1 aqueous alteration in CM carbonaceous chondrites: Implications for the evolution of water-rich asteroids
The CM carbonaceous chondrite meteorites experienced aqueous alteration in the early solar system. They range from mildly altered type 2 to almost completely hydrated type 1 chondrites, and offer a record of geochemical conditions on waterârich asteroids. We show that CM1 chondrites contain abundant (84â91 vol%) phyllosilicate, plus olivine (4â8 vol%), magnetite (2â3 vol%), Feâsulfide (120 °C), although higher water/rock ratios may also have played a role. The modal data provide constraints for interpreting the composition of asteroids and the mineralogy of samples returned from these bodies. We predict that âCM1âlikeâ asteroids, as has been proposed for Bennuâtarget for the OSIRISâREx missionâwill have a high abundance of Mgârich phyllosilicates and Feâoxides, but be depleted in calcite
Petrography, stable isotope compositions, microRaman spectroscopy, and presolar components of Roberts Massif 04133: A reduced CV3 carbonaceous chondrite
Here, we report the mineralogy, petrography, C-N-O-stable isotope compositions, degree of disorder of organic matter, and abundances of presolar components of the chondrite Roberts Massif (RBT) 04133 using a coordinated, multitechnique approach. The results of this study are inconsistent with its initial classification as a Renazzo-like carbonaceous chondrite, and strongly support RBT 04133 being a brecciated, reduced petrologic type >3.3 Vigarano-like carbonaceous (CV) chondrite. RBT 04133 shows no evidence for aqueous alteration. However, it is mildly thermally altered (up to approximately 440 °C); which is apparent in its whole-rock C and N isotopic compositions, the degree of disorder of C in insoluble organic matter, low presolar grain abundances, minor element compositions of Fe,Ni metal, chromite compositions and morphologies, and the presence of unequilibrated silicates. Sulfides within type I chondrules from RBT 04133 appear to be pre-accretionary (i.e., did not form via aqueous alteration), providing further evidence that some sulfide minerals formed prior to accretion of the CV chondrite parent body. The thin section studied contains two reduced CV3 lithologies, one of which appears to be more thermally metamorphosed, indicating that RBT 04133, like several other CV chondrites, is a breccia and thus experienced impact processing. Linear foliation of chondrules was not observed implying that RBT 04133 did not experience high velocity impacts that could lead to extensive thermal metamorphism. Presolar silicates are still present in RBT 04133, although presolar SiC grain abundances are very low, indicating that the progressive destruction or modification of presolar SiC grains begins before presolar silicate grains are completely unidentifiable
A Global Fireball Observatory
The world's meteorite collections contain a very rich picture of what the
early Solar System would have been made of, however the lack of spatial context
with respect to their parent population for these samples is an issue. The
asteroid population is equally as rich in surface mineralogies, and mapping
these two populations (meteorites and asteroids) together is a major challenge
for planetary science. Directly probing asteroids achieves this at a high cost.
Observing meteorite falls and calculating their pre-atmospheric orbit on the
other hand, is a cheaper way to approach the problem. The Global Fireball
Observatory (GFO) collaboration was established in 2017 and brings together
multiple institutions (from Australia, USA, Canada, Morocco, Saudi Arabia, the
UK, and Argentina) to maximise the area for fireball observation time and
therefore meteorite recoveries. The members have a choice to operate
independently, but they can also choose to work in a fully collaborative manner
with other GFO partners. This efficient approach leverages the experience
gained from the Desert Fireball Network (DFN) pathfinder project in Australia.
The state-of-the art technology (DFN camera systems and data reduction) and
experience of the support teams is shared between all partners, freeing up time
for science investigations and meteorite searching. With all networks combined
together, the GFO collaboration already covers 0.6% of the Earth's surface for
meteorite recovery as of mid-2019, and aims to reach 2% in the early 2020s. We
estimate that after 5 years of operation, the GFO will have observed a fireball
from virtually every meteorite type. This combined effort will bring new,
fresh, extra-terrestrial material to the labs, yielding new insights about the
formation of the Solar System.Comment: Accepted in PSS. 19 pages, 9 figure