Information-driven protein-DNA docking using HADDOCK: it is a matter of flexibility

Abstract

Intrinsic flexibility of DNA has hampered the development of efficient protein−DNA docking methods. In this study we extend HADDOCK (High Ambiguity Driven DOCKing) [C. Dominguez, R. Boelens and A. M. J. J. Bonvin (2003) J. Am. Chem. Soc. 125, 1731–1737] to explicitly deal with DNA flexibility. HADDOCK uses non-structural experimental data to drive the docking during a rigid-body energy minimization, and semi-flexible and water refinement stages. The latter allow for flexibility of all DNA nucleotides and the residues of the protein at the predicted interface. We evaluated our approach on the monomeric repressor−DNA complexes formed by bacteriophage 434 Cro, the Escherichia coli Lac headpiece and bacteriophage P22 Arc. Starting from unbound proteins and canonical B-DNA we correctly predict the correct spatial disposition of the complexes and the specific conformation of the DNA in the published complexes. This information is subsequently used to generate a library of pre-bent and twisted DNA structures that served as input for a second docking round. The resulting top ranking solutions exhibit high similarity to the published complexes in terms of root mean square deviations, intermolecular contacts and DNA conformation. Our two-stage docking method is thus able to successfully predict protein−DNA complexes from unbound constituents using non-structural experimental data to drive the docking.

Structure of p15PAF–PCNA complex and implications for clamp sliding during DNA replication and repair

“…The 24 bp DNA duplex in regular B conformation was then placed within the channel, and the whole ternary complex structure was refined by simulated annealing and energy minimization using loose and ambiguous distance restraints between DNA and PCNA in the HADDOCK refinement protocol 56 . Atoms at the interface (within 6.5 Å) were allowed to sample additional conformations during a semi-flexible simulated annealing, and further refinement in explicit water solvent was performed.…”

Aptamers—A Promising Approach for Sensing of Biothreats Using Different Bioinformatics Tools

“…3D-DART uses the DNA rebuild functionality of the well-known software package 3DNA [24,25]. The sequences obtained from the analysis were chosen for the docking proposes and the using two webserver were compared and then by using the HADDOCK [26,27] we had chosen those sequences that were having a low binding energy. HADDOCK (High Ambiguity Driven protein-protein DOCKing) is an online software that provide information-driven flexible docking approach for the modelling of biomolecular complexes [23,24].…”

Nucleotide docking: prediction of reactant state complexes for ribonuclease enzymes

“…To this end, several publications have recently appeared comparing and evaluating the different docking tools for a given enzyme-ligand combination [6][7][8][9]. Almost all papers, however, consider protein-based docking of small ligand molecules or proteinprotein docking, with the exception of van Dijk et al who have recently developed a new method for protein-DNA docking [10][11][12]. Predicting the correct binding between proteins and RNA oligonucleotide chains is of growing interest [13][14][15], although rarely described in the literature.…”