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Metadynamics calculations of large chemical systems with ab initio methods are computationally prohibitive due to the extensive sampling required to simulate the large degrees of freedom in these systems. To address this computational bottleneck, we utilized a GPU-enhanced density functional tight binding (DFTB) approach on a massively parallelized cloud computing platform to efficiently calculate the thermodynamics and metadynamics of biochemical systems. To first validate our approach, we calculated the free-energy surfaces of alanine dipeptide and showed that our GPU-enhanced DFTB calculations qualitatively agree with computationally-intensive hybrid DFT benchmarks, whereas classical force fields give significant errors. Most importantly, we show that our GPU-accelerated DFTB calculations are significantly faster than previous approaches by up to two orders of magnitude. To further extend our GPU-enhanced DFTB approach, we also carried out a 10 ns metadynamics simulation of remdesivir, which is prohibitively out of reach for routine DFT-based metadynamics calculations. We find that the free-energy surfaces of remdesivir obtained from DFTB and classical force fields differ significantly, where the latter overestimates the internal energy contribution of high free-energy states. Taken together, our benchmark tests, analyses, and extensions to large biochemical systems highlight the use of GPU-enhanced DFTB simulations for efficiently predicting the free-energy surfaces/thermodynamics of large biochemical systems. 

Abstract Living amphibians (Lissamphibia) include frogs and salamanders (Batrachia) and the limbless worm-like caecilians (Gymnophiona). The estimated Palaeozoic era gymnophionan–batrachian molecular divergence 1 suggests a major gap in the record of crown lissamphibians prior to their earliest fossil occurrences in the Triassic period 2–6 . Recent studies find a monophyletic Batrachia within dissorophoid temnospondyls 7–10 , but the absence of pre-Jurassic period caecilian fossils 11,12 has made their relationships to batrachians and affinities to Palaeozoic tetrapods controversial 1,8,13,14 . Here we report the geologically oldest stem caecilian—a crown lissamphibian from the Late Triassic epoch of Arizona, USA—extending the caecilian record by around 35 million years. These fossils illuminate the tempo and mode of early caecilian morphological and functional evolution, demonstrating a delayed acquisition of musculoskeletal features associated with fossoriality in living caecilians, including the dual jaw closure mechanism 15,16 , reduced orbits 17 and the tentacular organ 18 . The provenance of these fossils suggests a Pangaean equatorial origin for caecilians, implying that living caecilian biogeography reflects conserved aspects of caecilian function and physiology 19 , in combination with vicariance patterns driven by plate tectonics 20 . These fossils reveal a combination of features that is unique to caecilians alongside features that are shared with batrachian and dissorophoid temnospondyls, providing new and compelling evidence supporting a single origin of living amphibians within dissorophoid temnospondyls. 

Metoposaurids are a clade of large-bodied temnospondyls commonly found in non-marine Late Triassic deposits across northern Pangea. Three taxa are known from North America: Anaschisma browni , Apachesaurus gregorii , and “ Metoposaurus ” bakeri . While the osteology of most metoposaurids has been recently revised, that of a few taxa, including “ Metoposaurus ” bakeri remains poorly characterized. This taxon was formally described in 1931 as “ Buettneria bakeri ,” and its taxonomy has remained in flux ever since then. “ Metoposaurus ” bakeri is the earliest appearing metoposaurid in North America (Carnian of Texas), and Metoposaurus has frequently been utilized as an index taxon of the Otischalkian estimated holochron (‘land vertebrate faunachron’) and for biostratigraphic correlations with other geographic regions. The taxonomy of this species is therefore relevant for both taxonomic experts and biostratigraphers. Here we redescribe all material from the type locality of “ M .” bakeri , the Elkins Place bone bed, and perform a phylogenetic analysis using a revised matrix assembled from several previous studies. Anatomical comparisons and phylogenetic analyses do not support placement in either Metoposaurus , a taxon otherwise only found in Europe, or Anaschisma , the only other large-bodied taxon from North America. Therefore, we erect a new genus, Buettnererpeton gen. nov., to accommodate this species. Metoposaurus is consequently absent from North America, and this genus cannot be used in global biostratigraphy. Phylogenetic analyses provide evidence that the phylogeny of the Metoposauridae remains extremely labile, with drastic differences in topological resolution and structure being linked to just a handful of characters and scores. Metoposaurids’ morphological conservatism and the increased recognition of intraspecific variation thus continue to be major confounds to elucidating the evolutionary history of this clade. 

Across herbivorous insect clades, species richness and host-use diversity tend to positively covary. This could be because host-use divergence drives speciation, or because it raises the ecological limits on species richness. To evaluate these hypotheses, we performed phylogenetic path model analyses of the species diversity of Nearctic aphids. Here, we show that variation in the species richness of aphid clades is caused mainly by host-use divergence, whereas variation in speciation rates is caused more by divergence in non-host-related niche variables. Aphid speciation is affected by both the evolution of host and non-host-related niche components, but the former is largely caused by the latter. Thus, our analyses suggest that host-use divergence can both raise the ecological limits on species richness and drive speciation, although in the latter case, host-use divergence tends to be a step along the causal path leading from non-host-related niche evolution to speciation.