Section: Research Program
Classifying and Mining Protein Structures and Protein Interactions
The scientific discovery process is very often based on cycles of measurement, classification, and generalisation. It is easy to argue that this is especially true in the biological sciences. The proteins that exist today represent the molecular product of some three billion years of evolution. Therefore, comparing protein sequences and structures is important for understanding their functional and evolutionary relationships , . There is now overwhelming evidence that all living organisms and many biological processes share a common ancestry in the tree of life. Historically, much of bioinformatics research has focused on developing mathematical and statistical algorithms to process, analyse, annotate, and compare protein and DNA sequences because such sequences represent the primary form of information in biological systems. However, there is growing evidence that structure-based methods can help to predict networks of protein-protein interactions (PPIs) with greater accuracy than those which do not use structural evidence , . Therefore, developing techniques which can mine knowledge of protein structures and their interactions is an important way to enhance our knowledge of biology .
Formalising and Exploiting Domain Knowledge
Concerning protein structure classification, we aim to explore novel classification paradigms to circumvent the problems encountered with existing hierarchical classifications of protein folds and domains. In particular it will be interesting to set up fuzzy clustering methods taking advantage of our previous work on gene functional classification , but instead using Kpax domain-domain similarity matrices. A non-trivial issue with fuzzy clustering is how to handle similarity rather than mathematical distance matrices, and how to find the optimal number of clusters, especially when using a non-Euclidean similarity measure. We will adapt the algorithms and the calculation of quality indices to the Kpax similarity measure. More fundamentally, it will be necessary to integrate this classification step in the more general process leading from data to knowledge called Knowledge Discovery in Databases (KDD) .
Another example where domain knowledge can be useful is during result interpretation: several sources of knowledge have to be used to explicitly characterise each cluster and to help decide its validity. Thus, it will be useful to be able to express data models, patterns, and rules in a common formalism using a defined vocabulary for concepts and relationships. Existing approaches such as the Molecular Interaction (MI) format  developed by the Human Genome Organization (HUGO) mostly address the experimental wet lab aspects leading to data production and curation . A different point of view is represented in the Interaction Network Ontology (INO), a community-driven ontology that aims to standardise and integrate data on interaction networks and to support computer-assisted reasoning . However, this ontology does not integrate basic 3D concepts and structural relationships. Therefore, extending such formalisms and symbolic relationships will be beneficial, if not essential, when classifying the 3D shapes of proteins at the domain family level.
Domain family classification is also relevant for studying domain-domain interactions (DDI). Our previous work on Knowledge-Based Docking (KBDOCK, ,  will be updated and extended using newly published DDIs. Methods for inferring new DDIs from existing protein-protein interactions (PPIs) will be developped. Efforts should be made for validating such inferred DDIs so that they can be used to enrich DDI classification and predict new PPIs.
In parallel, we also intend to design algorithms for leveraging information embedded in biological knowledge graphs (also known as complex networks). Knowledge graphs mostly represent PPIs, integrated with various properties attached to proteins, such as pathways, drug binding or relation with diseases. Setting up similarity measures for proteins in a knowledge graph is a difficult challenge. Our objective is to extract useful knowledge from such graphs in order to better understand and highlight the role of multi-component assemblies in various types of cell or organisms. Ultimately, knowledge graphs can be used to model and simulate the functioning of such molecular machinery in the context of the living cell, under physiological or pathological conditions.
Function Annotation in large protein graphs
Knowledge of the functional properties of proteins can shed considerable light on how they might interact. However, huge numbers of protein sequences in public databases such as UniProt/TrEMBL lack any functional annotation, and the functional annotation of such sequences is a highly challenging problem. We are developing graph-based and machine learning techniques to annotate automatically the available unannotated sequences with functional properties such as EC numbers and Gene Ontology (GO) terms (note that these terms are organized hierarchically allowing generalization/specialization reasoning). The idea is to transfer annotations from expert-reviewed sequences present in the UniProt/SwissProt database (about 560 thousands entries) to unreviewed sequences present in the UniProt/TrEMBL database (about 80% of 180 millions entries). For this, we have to learn from the UniProt/SwissProt database how to compute the similarity of proteins sharing identical or similar functional annotations. Various similarity measures can be tested using cross-validation approches in the UniProt/SwissProt database. For instance, we can use primary sequence or domain signature similarities. More complex similarities can be computed with graph-embedding techniques.