Flexible Macromolecular Docking

Meeting website

Organisers:

Chantal Prévost: Laboratoire de Biochimie Théorique - CNRS UPR 9080 - IBPC, Paris France
Michael Sternberg: Department of Biology and Biochemistry , Imperial College of Science, London, UK
Joël Janin: Laboratoire d'Enzymologie et Biochimie Structurales , CNRS 91198, Gif-sur-Yvette, France

The last 25 years have witnessed the development of potent algorithms for docking macromolecules. Launched in 2001, the CAPRI contest (Critical Assessment of PRediction of Interactions)provides evaluation of these methods on a common ground and incentives new methodology development. The motivation is to be able to build three-dimensional structures of molecular machineries (the biological active species) starting from their separate macromolecular elements. The structure of these elements is generally available in their unbound form and may arise from precise X-ray or NMR structure resolution, but also from low resolution EM reconstruction or from homology modeling. In addition to side-chain fluctuations likely to occur between the free and bound forms, it is possible that the main chain undergoes conformational changes during association. Structural elements may also be missing in the unbound form, particularly in the case of low resolution structures. Proteins loops are generally poorly defined in structures resulting from homology modelling.

Further improvement of docking methods necessitates to take into account the flexibility of the receptor as well as that of the ligand macromolecule. This is a difficult task to achieve while conserving the search rapidity necessary for post-genomics applications.

Although they are not numerous, methodologies for considering macromolecule flexibility during docking are being developed. In these methods, different levels of flexibility are considered: protein side-chains, protein loops, domain movements. Flexibility is introduced whether at the refinement stage or within the docking process itself.

The object of this workshop is to bring together the groups which have experienced some of these aspects of flexible docking in order to share the experience accumulated by each of them, to identify the difficulties inherent to flexible docking and to tackle the next steps to be performed in the field. Representants from neighboring fields, particularly small molecule docking and protein folding, will also bring their experience of protein flexibility.

Venue:

CECAM center (European Centre for Atomic and Molecular Computations) in Lyon, France.

Dates:

April 28-30 2004

Programme:

The following topics would be discussed :

• Presentation and analysis of the possible types of deformations which can be expected to occur within macromolecules during their association;
• Analysis of the impact of such deformations on the results of the Capri Contest; examples where conformational changes have or have not impeded good prediction;
• How flexibility is accounted for in the present docking methods :
  - implicitly or explicitly
  - at the level of side-chains, loops or domain
  - at the refinement stage or during the docking process
  The advantages and/or problems related with each level of representation will be discussed, in terms of prediction efficiency and processing time;
• Possible methods that can be used to treat protein flexibility at different levels : local or global, full-atom or reduced representation, harmonic or anharmonic movements; the experience accumulated in neighboring fields, small ligand docking or protein folding, will be discussed.
  

Registration:

See workshop website