Abstract Motivation The success of genome sequencing techniques has resulted in rapid explosion of protein sequences. Collections of multiple homologous sequences can provide critical information to the modeling of structure and function of unknown proteins. There are however no standard and efficient pipeline available for sensitive multiple sequence alignment (MSA) collection. This is particularly challenging when large whole-genome and metagenome databases are involved. Results We developed DeepMSA, a new open-source method for sensitive MSA construction, which has homologous sequences and alignments created from multi-sources of whole-genome and metagenome databases through complementary hidden Markov model algorithms. The practical usefulness of the pipeline was examined in three large-scale benchmark experiments based on 614 non-redundant proteins. First, DeepMSA was utilized to generate MSAs for residue-level contact prediction by six coevolution and deep learning-based programs, which resulted in an accuracy increase in long-range contacts by up to 24.4% compared to the default programs. Next, multiple threading programs are performed for homologous structure identification, where the average TM-score of the template alignments has over 7.5% increases with the use of the new DeepMSA profiles. Finally, DeepMSA was used for secondary structure prediction and resulted in statistically significant improvements in the Q3 accuracy. It is notedmore »
The choice of sequence homologs included in multiple sequence alignments has a dramatic impact on evolutionary conservation analysis
The analysis of sequence conservation patterns has been widely utilized to identify functionally important (catalytic and ligand-binding) protein residues for over a half-century. Despite decades of development, on average state-of-the-art non-template-based functional residue prediction methods must predict ∼25% of a protein’s total residues to correctly identify half of the protein’s functional site residues. The overwhelming proportion of false positives results in reported ‘F-Scores’ of ∼0.3. We investigated the limits of current approaches, focusing on the so-far neglected impact of the specific choice of homologs included in multiple sequence alignments (MSAs).
The limits of conservation-based functional residue prediction were explored by surveying the binding sites of 1023 proteins. A straightforward conservation analysis of MSAs composed of randomly selected homologs sampled from a PSI-BLAST search achieves average F-Scores of ∼0.3, a performance matching that reported by state-of-the-art methods, which often consider additional features for the prediction in a machine learning setting. Interestingly, we found that a simple combinatorial MSA sampling algorithm will in almost every case produce an MSA with an optimal set of homologs whose conservation analysis reaches average F-Scores of ∼0.6, doubling state-of-the-art performance. We also show that this is nearly at the theoretical limit of possible performance given more »
Supplementary data are available at Bioinformatics online.
- Publication Date:
- NSF-PAR ID:
- 10393456
- Journal Name:
- Bioinformatics
- Volume:
- 35
- Issue:
- 1
- Page Range or eLocation-ID:
- p. 12-19
- ISSN:
- 1367-4803
- Publisher:
- Oxford University Press
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract Summary A new dynamic community identifier (DCI) is presented that relies upon protein residue dynamic cross-correlations generated by Gaussian elastic network models to identify those residue clusters exhibiting motions within a protein. A number of examples of communities are shown for diverse proteins, including GPCRs. It is a tool that can immediately simplify and clarify the most essential functional moving parts of any given protein. Proteins usually can be subdivided into groups of residues that move as communities. These are usually densely packed local sub-structures, but in some cases can be physically distant residues identified to be within the same community. The set of these communities for each protein are the moving parts. The ways in which these are organized overall can aid in understanding many aspects of functional dynamics and allostery. DCI enables a more direct understanding of functions including enzyme activity, action across membranes and changes in the community structure from mutations or ligand binding. The DCI server is freely available on a web site (https://dci.bb.iastate.edu/).
Supplementary information Supplementary data are available at Bioinformatics online.
-
Ponty, Yann (Ed.)Abstract Motivation Detecting subtle biologically relevant patterns in protein sequences often requires the construction of a large and accurate multiple sequence alignment (MSA). Methods for constructing MSAs are usually evaluated using benchmark alignments, which, however, typically contain very few sequences and are therefore inappropriate when dealing with large numbers of proteins. Results eCOMPASS addresses this problem using a statistical measure of relative alignment quality based on direct coupling analysis (DCA): To maintain protein structural integrity over evolutionary time, substitutions at one residue position typically result in compensating substitutions at other positions. eCOMPASS computes the statistical significance of the congruence between high scoring directly coupled pairs and 3D contacts in corresponding structures, which depends upon properly aligned homologous residues. We illustrate eCOMPASS using both simulated and real MSAs. Availability and Implementation The eCOMPASS executable, C ++ open source code and input data sets are available at https://www.igs.umaryland.edu/labs/neuwald/software/compass. Supplementary information Supplementary data are available at Bioinformatics online.
-
Abstract Motivation Experimental biologists, biocurators, and computational biologists all play a role in characterizing a protein’s function. The discovery of protein function in the laboratory by experimental scientists is the foundation of our knowledge about proteins. Experimental findings are compiled in knowledgebases by biocurators to provide standardized, readily accessible, and computationally amenable information. Computational biologists train their methods using these data to predict protein function and guide subsequent experiments. To understand the state of affairs in this ecosystem, centered here around protein function prediction, we surveyed scientists from these three constituent communities.
Results We show that the three communities have common but also idiosyncratic perspectives on the field. Most strikingly, experimentalists rarely use state-of-the-art prediction software, but when presented with predictions, report many to be surprising and useful. Ontologies appear to be highly valued by biocurators, less so by experimentalists and computational biologists, yet controlled vocabularies bridge the communities and simplify the prediction task. Additionally, many software tools are not readily accessible and the predictions presented to the users can be broad and uninformative. We conclude that to meet both the social and technical challenges in the field, a more productive and meaningful interaction between members of the core communities is necessary.
-
Abstract Motivation Accurately predicting drug–target interactions (DTIs) in silico can guide the drug discovery process and thus facilitate drug development. Computational approaches for DTI prediction that adopt the systems biology perspective generally exploit the rationale that the properties of drugs and targets can be characterized by their functional roles in biological networks.
Results Inspired by recent advance of information passing and aggregation techniques that generalize the convolution neural networks to mine large-scale graph data and greatly improve the performance of many network-related prediction tasks, we develop a new nonlinear end-to-end learning model, called NeoDTI, that integrates diverse information from heterogeneous network data and automatically learns topology-preserving representations of drugs and targets to facilitate DTI prediction. The substantial prediction performance improvement over other state-of-the-art DTI prediction methods as well as several novel predicted DTIs with evidence supports from previous studies have demonstrated the superior predictive power of NeoDTI. In addition, NeoDTI is robust against a wide range of choices of hyperparameters and is ready to integrate more drug and target related information (e.g. compound–protein binding affinity data). All these results suggest that NeoDTI can offer a powerful and robust tool for drug development and drug repositioning.
Availability and implementation The source code and datamore »
Supplementary information Supplementary data are available at Bioinformatics online.
