Abstract Protein–protein interaction (PPI) networks represent complex intra-cellular protein interactions, and the presence or absence of such interactions can lead to biological changes in an organism. Recent network-based approaches have shown that a phenotype’s PPI network’s resilience to environmental perturbations is related to its placement in the tree of life; though we still do not know how or why certain intra-cellular factors can bring about this resilience. Here, we explore the influence of gene expression and network properties on PPI networks’ resilience. We use publicly available data of PPIs for E. coli , S. cerevisiae , and H. sapiens , where we compute changes in network resilience as new nodes (proteins) are added to the networks under three node addition mechanisms—random, degree-based, and gene-expression-based attachments. By calculating the resilience of the resulting networks, we estimate the effectiveness of these node addition mechanisms. We demonstrate that adding nodes with gene-expression-based preferential attachment (as opposed to random or degree-based) preserves and can increase the original resilience of PPI network in all three species, regardless of gene expression distribution or network structure. These findings introduce a general notion of prospective resilience , which highlights the key role of network structures in understanding the evolvability of phenotypic traits.
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On the Planarity of Validated Complexes of Model Organisms in Protein-Protein Interaction Networks
Leveraging protein-protein interaction networks to identify groups of proteins and their common functionality is an important problem in bioinformatics. Systems-level analysis of protein-protein interactions is made possible through network science and modeling of high-throughput data. From these analyses, small protein complexes are traditionally represented graphically as complete graphs or dense clusters of nodes. However, there are certain graph theoretic properties that have not been extensively studied in PPI networks, especially as they pertain to cluster discovery, such as planarity. Planarity of graphs have been used to reflect the physical constraints of real-world systems outside of bioinformatics, in areas such as mapping and imaging.
Here, we investigate the planarity property in network models of protein complexes. We hypothesize that complexes represented as PPI subgraphs will tend to be planar, reflecting the actual physical interface and limits of components in the complex. When testing the planarity of known complex subgraphs in S. cerevisiae and selected mammalian PPIs, we find that a majority of validated complexes possess this planar property. We discuss the biological motivation of planar versus nonplanar subgraphs, observing that planar subgraphs tend to have longer protein components. Functional classification of planar versus nonplanar complex subgraphs reveals differences in annotation of these groups relating to cellular component organization, structural molecule activity, catalytic activity, and nucleic acid binding. These results provide a new quantitative and biologically motivated measure of real protein complexes in the network model, important for the development of future complex-finding algorithms in PPIs. Accounting for this property paves the way to new means for discovering new protein complexes and uncovering the functionality of unknown or novel proteins.
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- Award ID(s):
- 1916084
- NSF-PAR ID:
- 10187223
- Date Published:
- Journal Name:
- Internal Conference on Computational Science ICCS 2020
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Yann, Ponty (Ed.)Abstract Motivation The study of the evolutionary history of biological networks enables deep functional understanding of various bio-molecular processes. Network growth models, such as the Duplication–Mutation with Complementarity (DMC) model, provide a principled approach to characterizing the evolution of protein–protein interactions (PPIs) based on duplication and divergence. Current methods for model-based ancestral network reconstruction primarily use greedy heuristics and yield sub-optimal solutions. Results We present a new Integer Linear Programming (ILP) solution for maximum likelihood reconstruction of ancestral PPI networks using the DMC model. We prove the correctness of our solution that is designed to find the optimal solution. It can also use efficient heuristics from general-purpose ILP solvers to obtain multiple optimal and near-optimal solutions that may be useful in many applications. Experiments on synthetic data show that our ILP obtains solutions with higher likelihood than those from previous methods, and is robust to noise and model mismatch. We evaluate our algorithm on two real PPI networks, with proteins from the families of bZIP transcription factors and the Commander complex. On both the networks, solutions from our ILP have higher likelihood and are in better agreement with independent biological evidence from other studies. Availability and implementation A Python implementation is available at https://bitbucket.org/cdal/network-reconstruction. Supplementary information Supplementary data are available at Bioinformatics online.more » « less
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Abstract Motivation Most proteins perform their biological functions through interactions with other proteins in cells. Amino acid mutations, especially those occurring at protein interfaces, can change the stability of protein–protein interactions (PPIs) and impact their functions, which may cause various human diseases. Quantitative estimation of the binding affinity changes (ΔΔGbind) caused by mutations can provide critical information for protein function annotation and genetic disease diagnoses.
Results We present SSIPe, which combines protein interface profiles, collected from structural and sequence homology searches, with a physics-based energy function for accurate ΔΔGbind estimation. To offset the statistical limits of the PPI structure and sequence databases, amino acid-specific pseudocounts were introduced to enhance the profile accuracy. SSIPe was evaluated on large-scale experimental data containing 2204 mutations from 177 proteins, where training and test datasets were stringently separated with the sequence identity between proteins from the two datasets below 30%. The Pearson correlation coefficient between estimated and experimental ΔΔGbind was 0.61 with a root-mean-square-error of 1.93 kcal/mol, which was significantly better than the other methods. Detailed data analyses revealed that the major advantage of SSIPe over other traditional approaches lies in the novel combination of the physical energy function with the new knowledge-based interface profile. SSIPe also considerably outperformed a former profile-based method (BindProfX) due to the newly introduced sequence profiles and optimized pseudocount technique that allows for consideration of amino acid-specific prior mutation probabilities.
Availability and implementation Web-server/standalone program, source code and datasets are freely available at https://zhanglab.ccmb.med.umich.edu/SSIPe and https://github.com/tommyhuangthu/SSIPe.
Supplementary information Supplementary data are available at Bioinformatics online.
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Abstract Background: In bioinformatics, network alignment algorithms have been applied to protein-protein interaction (PPI) networks to discover evolutionary conserved substructures at the system level. However, most previous methods aim to maximize the similarity of aligned proteins in pairwise networks, while concerning little about the feature of connectivity in these substructures, such as the protein complexes. Results: In this paper, we identify the problem of finding conserved protein complexes, which requires the aligned proteins in a PPI network to form a connected subnetwork. By taking the feature of connectivity into consideration, we propose ConnectedAlign, an efficient method to find conserved protein complexes from multiple PPI networks. The proposed method improves the coverage significantly without compromising of the consistency in the aligned results. In this way, the knowledge of protein complexes in well-studied species can be extended to that of poor-studied species. Conclusions: We conducted extensive experiments on real PPI networks of four species, including human, yeast, fruit fly and worm. The experimental results demonstrate dominant benefits of the proposed method in finding protein complexes across multiple species.more » « less
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Abstract Motivation Sequence-based protein–protein interaction (PPI) prediction represents a fundamental computational biology problem. To address this problem, extensive research efforts have been made to extract predefined features from the sequences. Based on these features, statistical algorithms are learned to classify the PPIs. However, such explicit features are usually costly to extract, and typically have limited coverage on the PPI information.
Results We present an end-to-end framework, PIPR (Protein–Protein Interaction Prediction Based on Siamese Residual RCNN), for PPI predictions using only the protein sequences. PIPR incorporates a deep residual recurrent convolutional neural network in the Siamese architecture, which leverages both robust local features and contextualized information, which are significant for capturing the mutual influence of proteins sequences. PIPR relieves the data pre-processing efforts that are required by other systems, and generalizes well to different application scenarios. Experimental evaluations show that PIPR outperforms various state-of-the-art systems on the binary PPI prediction problem. Moreover, it shows a promising performance on more challenging problems of interaction type prediction and binding affinity estimation, where existing approaches fall short.
Availability and implementation The implementation is available at https://github.com/muhaochen/seq_ppi.git.
Supplementary information Supplementary data are available at Bioinformatics online.
- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Conference Paper:
- https://doi.org/10.1007/978-3-030-50371-0_48
