CECAM workshop on Flexible Macromolecular Docking
April 28-30, 2004
Lyon, France


Presentation    |   Program    |    Participants   |    Scientific Report    |    Outdoor Meeting    |    CECAM home page


 Chantal Prévost

 Laboratoire de Biochimie Théorique
 13, rue Pierre et Marie Curie, 
 75005 Paris, France
 Phone : +33 (0)1 58 41 51 65
 Fax : +33 (0)1 58 41 50 26

 Michael J.E. Sternberg

 Structural Bioinformatics Group
 Biochemistry Building
 Department of Biological Sciences 
 Imperial College 
 London SW7 2AY, U.K.
 Phone : +44 (0)20 7594 5212
 Fax : +44 (0)20 7594 5264

Joël Janin

 Laboratoire d'Enzymologie et 
 Biochimie Structurales
 UPR 9063
 91198 Gif-sur-Yvette
 Phone : +33 (0)1 69 82 34 77
 Fax : +33 (0)1 69 82 31 29

Scientific background

The last 25 years have witnessed the development of powerful algorithms for docking macromolecules [1 ]. Launched in 2001, the CAPRI experiment (Critical Assessment of PRediction of Interactions) provides evaluation of these methods on a set of defined targets and encourages new methodology development [2 ]. The motivation of such projects is to build three-dimensional structures of molecular assemblies (the biological active species) starting from their separate macromolecular elements. The structure of these elements are generally available in their unbound form and either from precise X-ray or NMR structure resolution, or from low resolution EM reconstruction or homology modeling. In addition to the side-chain fluctuations likely to occur between the free and bound forms, it is possible that the main chain may also undergo conformational changes during association [3]. Fragments may also be missing in the unbound form, particularly in the case of low resolution structures. Thus, proteins loops are generally poorly defined in structures resulting from homology modelling [4]. Further improvement of docking methods requires taking into account the flexibility of the receptor as well as that of the target macromolecule [5]. This is a difficult task to achieve while conserving the search rapidity necessary for post-genomic applications.

Motivation and objectives

Although they are not numerous, methodologies for modeling macromolecule flexibility during docking are being developed. In these methods, different levels of flexibility are considered: protein side-chains [6], protein loops [7], domain movements [8]. Flexibility is introduced either at the refinement stage or during the docking process itself. The object of this workshop is to bring together the groups which have experience in various aspects of flexible docking in order to share their knowledge, to identify the difficulties inherent to flexible docking and to tackle the next steps to be taken. Representatives from the neighbouring fields of small molecule docking and protein folding, will also participate.


Main topics

-    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 experiment; 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 domains
                -    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 representations, harmonic or anharmonic movements; the experience accumulated in the neighboring fields of small ligand docking or protein folding, will be discussed.