Section: Overall Objectives

Overall Objectives

This project in bioinformatics is mainly concerned with the molecular levels of organization in the cell, dealing principally with RNAs and proteins; we currently concentrate our efforts on structure, interactions, evolution and annotation and aim at a contribution to protein and RNA engineering. On the one hand, we study and develop methodological approaches for dealing with macromolecular structures and annotation: the challenge is to develop abstract models that are computationally tractable and biologically relevant. On the other hand, we apply these computational approaches to several particular problems arising in fundamental molecular biology. These problems, described below, raise different computer science issues. To tackle them, the project members rely on a common methodology for which our group has a significant experience. The trade-off between the biological accuracy of the model and the computational tractability or efficiency is to be addressed in a closed partnership with experimental biology groups.

We investigate the relations between nucleotide sequences, 3D structures and, finally, biochemichal function. All protein functions and many RNA functions are intimately related to the three-dimensional molecular structure. Therefore, we view structure prediction and sequence analysis as an integral part of gene annotation that we study simultaneously and that we plan to pursue on a RNAomic and proteomic scale. Our starting point is the sequence either ab initio or with knowledge such as a 3D structural template or ChIP-Chip experiments. We are interested in deciphering the information organization in DNA sequences and identifying the role played by gene products: proteins and RNA, including noncoding RNAs. A common toolkit of computational methods is developed, that relies notably on combinatorial algorithms, mathematical analysis of algorithms and data mining. One goal is to provide softwares or platform elements to predict either structures or structural and functional annotation. For instance, a by-product of 3D structure prediction for protein and RNA engineering is to allow to propose sequences with admissible structures. Statistical softwares for structural annotation are included in annotation tools developped by partners, notably our associate team Migec .

Our work is organized along two main axes. The first one is structure prediction, comparison and design engineering. The relation between nucleotide sequence and 3D macromolecular structure, and the relation between 3D structure and biochemical function are possibly the two foremost problems in molecular biology. There are considerable experimental difficulties in determining 3D structures to a high precision. Therefore, there is a crucial need for efficient computational methods for structure prediction, functional assignment and molecular engineering. A focus is given on both protein and RNA structures.

The second axis is structural and functional annotation, a special attention being paid to regulation. Structural annotation deals with the identification of genomic elements, e.g. genes, coding regions, non coding regions, regulatory motifs. Functional annotation consists in characterizing their function, e.g. attaching biological information to these genomic elements. Namely, it provides biochemical function, biological function, regulation and interactions involved and expression conditions. High-throughput technologies make automated annotation crucial. There is a need for relevant computational annotation methods that take into account as many characteristics of gene products as possible -intrinsic properties, evolutionary changes or relationships- and that can estimate the reliability of their own results.