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.
References
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.
