How to efficiently account for side chain flexibility and global motions
during docking

Martin Zacharias, International University Bremen,
 

Most current docking approaches to predict the binding geometry of protein-protein complexes use rigid protein partner structures. However, protein complex formation can involve both local conformational changes of side chains and loops at the protein-protein interface and global conformational relaxation of the protein partners. We have developed a docking approach that is based on energy minimization of translational and rotational degrees of freedom of protein partners and on a reduced protein representation allowing efficient search for docking minima. A multicopy approach is used to select the most favourable side-chain conformation at the protein-protein interface during the docking process [1]. To approximately account for possible global conformational adaptation a method has been developed that allows to relax the protein structure in pre-calculated flexible degrees of freedom (soft modes) during docking [2]. Such flexible modes can for example be obtained from molecular dynamics simulations or on the level of a reduced protein representation by employing an energy function that depends on the local protein density. Application of the approaches to test systems will be presented.

[1] Zacharias, M. 2003. Protein-protein docking with a reduced protein model accounting for side chain flexibility. Protein Sci. 12, 1271.
[2] Zacharias, M. 2004. Rapid protein-ligand docking using soft modes from molecular dynamics simulations to account for protein deformability:binding of FK506 to FKBP. Proteins 54, 759.