Improving protein docking with binding site prediction

Protein-protein and protein-ligand interactions are fundamental as many proteins mediate their biological function through these interactions. Many important applications follow directly from the identification of residues in the interfaces between protein-protein and protein-ligand interactions, such as drug design, protein mimetic engineering, elucidation of molecular pathways, and understanding of disease mechanisms. The identification of interface residues can also guide the docking process to build the structural model of protein-protein complexes. This dissertation focuses on developing computational approaches for protein-ligand and protein-protein binding site prediction and applying these predictions to improve protein-protein docking. First, we develop an automated approach LIGSITEcs to predict protein-ligand binding site, based on the notion of surface-solvent-surface events and the degree of conservation of the involved surface residues. We compare our algorithm to four other approaches, LIGSITE, CAST, PASS, and SURFNET, and evaluate all on a dataset of 48 unbound/bound structures and 210 bound-structures. LIGSITEcs performs slightly better than the other tools and achieves a success rate of 71% and 75%, respectively. Second, for protein-protein binding site, we develop metaPPI, a meta server for interface prediction. MetaPPI combines results from a number of tools, such as PPI_Pred, PPISP, PINUP, Promate, and SPPIDER, which predict enzyme-inhibitor interfaces with success rates of 23% to 55% and other interfaces with 10% to 28% on a benchmark dataset of 62 complexes. After refinement, metaPPI significantly improves prediction success rates to 70% for enzyme-inhibitor and 44% for other interfaces. Third, for protein-protein docking, we develop a FFT-based docking algorithm and system BDOCK, which includes specific scoring functions for specific types of complexes. BDOCK uses family-based residue interface propensities as a scoring function and obtains improvement factors of 4-30 for enzyme-inhibitor and 4-11 for antibody-antigen complexes in two specific SCOP families. Furthermore, the degrees of buriedness of surface residues are integrated into BDOCK, which improves the shape discriminator for enzyme-inhibitor complexes. The predicted interfaces from metaPPI are integrated as well, either during docking or after docking. The evaluation results show that reliable interface predictions improve the discrimination between near-native solutions and false positive. Finally, we propose an implicit method to deal with the flexibility of proteins by softening the surface, to improve docking for non enzyme-inhibitor complexes

Improving protein docking with binding site prediction

Protein-protein and protein-ligand interactions are fundamental as many proteins mediate their biological function through these interactions. Many important applications follow directly from the identification of residues in the interfaces between protein-protein and protein-ligand interactions, such as drug design, protein mimetic engineering, elucidation of molecular pathways, and understanding of disease mechanisms. The identification of interface residues can also guide the docking process to build the structural model of protein-protein complexes. This dissertation focuses on developing computational approaches for protein-ligand and protein-protein binding site prediction and applying these predictions to improve protein-protein docking. First, we develop an automated approach LIGSITEcs to predict protein-ligand binding site, based on the notion of surface-solvent-surface events and the degree of conservation of the involved surface residues. We compare our algorithm to four other approaches, LIGSITE, CAST, PASS, and SURFNET, and evaluate all on a dataset of 48 unbound/bound structures and 210 bound-structures. LIGSITEcs performs slightly better than the other tools and achieves a success rate of 71% and 75%, respectively. Second, for protein-protein binding site, we develop metaPPI, a meta server for interface prediction. MetaPPI combines results from a number of tools, such as PPI_Pred, PPISP, PINUP, Promate, and SPPIDER, which predict enzyme-inhibitor interfaces with success rates of 23% to 55% and other interfaces with 10% to 28% on a benchmark dataset of 62 complexes. After refinement, metaPPI significantly improves prediction success rates to 70% for enzyme-inhibitor and 44% for other interfaces. Third, for protein-protein docking, we develop a FFT-based docking algorithm and system BDOCK, which includes specific scoring functions for specific types of complexes. BDOCK uses family-based residue interface propensities as a scoring function and obtains improvement factors of 4-30 for enzyme-inhibitor and 4-11 for antibody-antigen complexes in two specific SCOP families. Furthermore, the degrees of buriedness of surface residues are integrated into BDOCK, which improves the shape discriminator for enzyme-inhibitor complexes. The predicted interfaces from metaPPI are integrated as well, either during docking or after docking. The evaluation results show that reliable interface predictions improve the discrimination between near-native solutions and false positive. Finally, we propose an implicit method to deal with the flexibility of proteins by softening the surface, to improve docking for non enzyme-inhibitor complexes

LIGSITE(csc): predicting ligand binding sites using the Connolly surface and degree of conservation

BACKGROUND: Identifying pockets on protein surfaces is of great importance for many structure-based drug design applications and protein-ligand docking algorithms. Over the last ten years, many geometric methods for the prediction of ligand-binding sites have been developed. RESULTS: We present LIGSITE(csc), an extension and implementation of the LIGSITE algorithm. LIGSITE(csc )is based on the notion of surface-solvent-surface events and the degree of conservation of the involved surface residues. We compare our algorithm to four other approaches, LIGSITE, CAST, PASS, and SURFNET, and evaluate all on a dataset of 48 unbound/bound structures and 210 bound-structures. LIGSITE(csc )performs slightly better than the other tools and achieves a success rate of 71% and 75%, respectively. CONCLUSION: The use of the Connolly surface leads to slight improvements, the prediction re-ranking by conservation to significant improvements of the binding site predictions. A web server for LIGSITE(csc )and its source code is available at scoppi.biotec.tu-dresden.de/pocket

A Systematic Review for Transformer-based Long-term Series Forecasting

The emergence of deep learning has yielded noteworthy advancements in time series forecasting (TSF). Transformer architectures, in particular, have witnessed broad utilization and adoption in TSF tasks. Transformers have proven to be the most successful solution to extract the semantic correlations among the elements within a long sequence. Various variants have enabled transformer architecture to effectively handle long-term time series forecasting (LTSF) tasks. In this article, we first present a comprehensive overview of transformer architectures and their subsequent enhancements developed to address various LTSF tasks. Then, we summarize the publicly available LTSF datasets and relevant evaluation metrics. Furthermore, we provide valuable insights into the best practices and techniques for effectively training transformers in the context of time-series analysis. Lastly, we propose potential research directions in this rapidly evolving field

DNA methylome analysis in Burkitt and follicular lymphomas identifies differentially methylated regions linked to somatic mutation and transcriptional control

Although Burkitt lymphomas and follicular lymphomas both have features of germinal center B cells, they are biologically and clinically quite distinct. Here we performed whole-genome bisulfite, genome and transcriptome sequencing in 13 IG-MYC translocation-positive Burkitt lymphoma, nine BCL2 translocation-positive follicular lymphoma and four normal germinal center B cell samples. Comparison of Burkitt and follicular lymphoma samples showed differential methylation of intragenic regions that strongly correlated with expression of associated genes, for example, genes active in germinal center dark-zone and light-zone B cells. Integrative pathway analyses of regions differentially methylated in Burkitt and follicular lymphomas implicated DNA methylation as cooperating with somatic mutation of sphingosine phosphate signaling, as well as the TCF3-ID3 and SWI/SNF complexes, in a large fraction of Burkitt lymphomas. Taken together, our results demonstrate a tight connection between somatic mutation, DNA methylation and transcriptional control in key B cell pathways deregulated differentially in Burkitt lymphoma and other germinal center B cell lymphomas

Improving protein docking with binding site prediction

Protein-protein and protein-ligand interactions are fundamental as many proteins mediate their biological function through these interactions. Many important applications follow directly from the identification of residues in the interfaces between protein-protein and protein-ligand interactions, such as drug design, protein mimetic engineering, elucidation of molecular pathways, and understanding of disease mechanisms. The identification of interface residues can also guide the docking process to build the structural model of protein-protein complexes. This dissertation focuses on developing computational approaches for protein-ligand and protein-protein binding site prediction and applying these predictions to improve protein-protein docking. First, we develop an automated approach LIGSITEcs to predict protein-ligand binding site, based on the notion of surface-solvent-surface events and the degree of conservation of the involved surface residues. We compare our algorithm to four other approaches, LIGSITE, CAST, PASS, and SURFNET, and evaluate all on a dataset of 48 unbound/bound structures and 210 bound-structures. LIGSITEcs performs slightly better than the other tools and achieves a success rate of 71% and 75%, respectively. Second, for protein-protein binding site, we develop metaPPI, a meta server for interface prediction. MetaPPI combines results from a number of tools, such as PPI_Pred, PPISP, PINUP, Promate, and SPPIDER, which predict enzyme-inhibitor interfaces with success rates of 23% to 55% and other interfaces with 10% to 28% on a benchmark dataset of 62 complexes. After refinement, metaPPI significantly improves prediction success rates to 70% for enzyme-inhibitor and 44% for other interfaces. Third, for protein-protein docking, we develop a FFT-based docking algorithm and system BDOCK, which includes specific scoring functions for specific types of complexes. BDOCK uses family-based residue interface propensities as a scoring function and obtains improvement factors of 4-30 for enzyme-inhibitor and 4-11 for antibody-antigen complexes in two specific SCOP families. Furthermore, the degrees of buriedness of surface residues are integrated into BDOCK, which improves the shape discriminator for enzyme-inhibitor complexes. The predicted interfaces from metaPPI are integrated as well, either during docking or after docking. The evaluation results show that reliable interface predictions improve the discrimination between near-native solutions and false positive. Finally, we propose an implicit method to deal with the flexibility of proteins by softening the surface, to improve docking for non enzyme-inhibitor complexes