PYTHIA: Deep Learning Approach for Local Protein Conformation Prediction

Protein Blocks (PBs) are a widely used structural alphabet describing local protein backbone conformation in terms of 16 possible conformational states, adopted by five consecutive amino acids. The representation of complex protein 3D structures as 1D PB sequences was previously successfully applied to protein structure alignment and protein structure prediction. In the current study, we present a new model, PYTHIA (predicting any conformation at high accuracy), for the prediction of the protein local conformations in terms of PBs directly from the amino acid sequence. PYTHIA is based on a deep residual inception-inside-inception neural network with convolutional block attention modules, predicting 1 of 16 PB classes from evolutionary information combined to physicochemical properties of individual amino acids. PYTHIA clearly outperforms the LOCUSTRA reference method for all PB classes and demonstrates great performance for PB prediction on particularly challenging proteins from the CASP14 free modelling category.

Stress tolerance enhancement via SPT15 base editing in Saccharomyces cerevisiae

Background Saccharomyces cerevisiae is widely used in traditional brewing and modern fermentation industries to produce biofuels, chemicals and other bioproducts, but challenged by various harsh industrial conditions, such as hyperosmotic, thermal and ethanol stresses. Thus, its stress tolerance enhancement has been attracting broad interests. Recently, CRISPR/Cas-based genome editing technology offers unprecedented tools to explore genetic modifications and performance improvement of S. cerevisiae. Results Here, we presented that the Target-AID (activation-induced cytidine deaminase) base editor of enabling C-to-T substitutions could be harnessed to generate in situ nucleotide changes on the S. cerevisiae genome, thereby introducing protein point mutations in cells. The general transcription factor gene SPT15 was targeted, and total 36 mutants with diversified stress tolerances were obtained. Among them, the 18 tolerant mutants against hyperosmotic, thermal and ethanol stresses showed more than 1.5-fold increases of fermentation capacities. These mutations were mainly enriched at the N-terminal region and the convex surface of the saddle-shaped structure of Spt15. Comparative transcriptome analysis of three most stress-tolerant (A140G, P169A and R238K) and two most stress-sensitive (S118L and L214V) mutants revealed common and distinctive impacted global transcription reprogramming and transcriptional regulatory hubs in response to stresses, and these five amino acid changes had different effects on the interactions of Spt15 with DNA and other proteins in the RNA Polymerase II transcription machinery according to protein structure alignment analysis. Conclusions Taken together, our results demonstrated that the Target-AID base editor provided a powerful tool for targeted in situ mutagenesis in S. cerevisiae and more potential targets of Spt15 residues for enhancing yeast stress tolerance.

Stress tolerance enhancement via SPT15 base editing in Saccharomyces cerevisiae

Background Saccharomyces cerevisiae is widely used in traditional brewing and modern fermentation industries to produce biofuels, chemicals and other bioproducts, but challenged by various harsh industrial conditions, such as hyperosmotic, thermal and ethanol stresses. Thus, its stress tolerance enhancement has been attracting broad interests. Recently, CRISPR/Cas-based genome editing technology offers unprecedented tools to explore genetic modifications and performance improvement of S. cerevisiae. Results Here, we presented that the Target-AID (activation-induced cytidine deaminase) base editor of enabling C-to-T substitutions could be harnessed to generate in situ nucleotide changes on the S. cerevisiae genome, thereby introducing protein point mutation in cells. The general transcription factor gene SPT15 was targeted, and total 36 mutants with diversified stress tolerances were obtained. Among them, the 18 tolerant mutants against hyperosmotic, thermal and ethanol stresses showed more than 1.5-fold increases of fermentation capacities. These mutations were mainly enriched at the N-terminal region and the convex surface of the saddle-shaped structure of Spt15. Comparative transcriptome analysis of three most stress-tolerant (A140G, P169A and R238K) and two most stress-sensitive (S118L and L214V) mutants revealed common and distinctive impacted global transcription reprogramming and transcriptional regulatory hubs in response to stresses, and these five amino acid changes had different effects on the interactions of Spt15 with DNA and other proteins in the RNA Polymerase II transcription machinery according to protein structure alignment analysis. Conclusions Taken together, our results demonstrated that the Target-AID base editor provided a powerful tool for targeted in situ mutagenesis in S. cerevisiae and more potential targets of Spt15 residues for enhancing yeast stress tolerance.

pmTM-align: scalable pairwise and multiple structure alignment with Apache Spark and OpenMP

Background Structure comparison can provide useful information to identify functional and evolutionary relationship between proteins. With the dramatic increase of protein structure data in the Protein Data Bank, computation time quickly becomes the bottleneck for large scale structure comparisons. To more efficiently deal with informative multiple structure alignment tasks, we propose pmTM-align, a parallel protein structure alignment approach based on mTM-align/TM-align. pmTM-align contains two stages to handle pairwise structure alignments with Spark and the phylogenetic tree-based multiple structure alignment task on a single computer with OpenMP. Results Experiments with the SABmark dataset showed that parallelization along with data structure optimization provided considerable speedup for mTM-align. The Spark-based structure alignments achieved near ideal scalability with large datasets, and the OpenMP-based construction of the phylogenetic tree accelerated the incremental alignment of multiple structures and metrics computation by a factor of about 2–5. Conclusions pmTM-align enables scalable pairwise and multiple structure alignment computing and offers more timely responses for medium to large-sized input data than existing alignment tools such as mTM-align.

FATCAT 2.0: towards a better understanding of the structural diversity of proteins

FATCAT 2.0 server (http://fatcat.godziklab.org/), provides access to a flexible protein structure alignment algorithm developed in our group. In such an alignment, rotations and translations between elements in the structure are allowed to minimize the overall root mean square deviation (RMSD) between the compared structures. This allows to effectively compare protein structures even if they underwent structural rearrangements in different functional forms, different crystallization conditions or as a result of mutations. The major update for the server introduces a new graphical interface, much faster database searches and several new options for visualization of the structural differences between proteins

Structural and Genetic Analysis of Coronaviruses Spike Proteins Suggest Pangolin as a Proximate Intermediate Host of SARS-CoV-2 (COVID-19)

During December 2019, a novel coronavirus named SARS-CoV-2 has emerged in Wuhan, China. The human to human transmission of this virus has also been established. The virus has so far infected more than 2 million people and spread over 200 countries. The World Health Organization (WHO) has declared COVID-19 a global health emergency due to its spread well beyond China. It has been established that this virus originates from bats and uses an intermediate host for transfer to humans. The knowledge about the intermediate host is important to find the virus shuttle mechanism to stop future outbreaks. For this, the genetic and structural analysis of coronaviruses spike proteins was performed using a computer-assisted approach.To conduct the In silico analysis, 43 sequences of spike protein belong to different species were retrieved from the NCBI nucleotide database. Pairwise and multiple sequence alignments were performed to check the similarities and differences of the retrieved sequences. Moreover, to highlight relationships among different species, phylogenetics analysis was performed using the MEGA software tool. In the end, protein structure alignment (superimposition) was performed against the reference structure by UCSF Chimera software. The results highlighted that the maximum similarity of human protein was found against Bat and Pangolinsequences. Moreover, among Bat and Pangolin, the highest similarity was found against pangolin based on phylogenetics analysis. These results suggest that SARS-CoV-2 transfers from bats to humans through pangolins.

FTIP: an accurate and efficient method for global protein surface comparison

Motivation Global protein surface comparison (GPSC) studies have been limited compared to other research works on protein structure alignment/comparison due to lack of real applications associated with GPSC. However, the technology advances in cryo-electron tomography (CET) have made methods to identify proteins from their surface shapes extremely useful. Results In this study, we developed a new method called Farthest point sampling (FPS)-enhanced Triangulation-based Iterative-closest-Point (ICP) (FTIP) for GPSC. We applied it to protein classification using only surface shape information. Our method first extracts a set of feature points from protein surfaces using FPS and then uses a triangulation-based efficient ICP algorithm to align the feature points of the two proteins to be compared. Tested on a benchmark dataset with 2329 proteins using nearest-neighbor classification, FTIP outperformed the state-of-the-art method for GPSC based on 3D Zernike descriptors. Using real and simulated cryo-EM data, we show that FTIP could be applied in the future to address problems in protein identification in CET experiments. Availability and implementation Programs/scripts we developed/used in the study are available at http://ani.stat.fsu.edu/∼yuan/index.fld/FTIP.tar.bz2. Supplementary information Supplementary data are available at Bioinformatics online.