Knowledge-Guided Docking of WW Domain Proteins and Flexible Ligands

Abstract

Abstract. Studies of interactions between protein domains and ligands are important in many aspects such as cellular signaling. We present a knowledge-guided approach for docking protein domains and flexible ligands. The approach is applied to the WW domain, a small protein module mediating signaling complexes which have been implicated in diseases such as muscular dystrophy and Liddle's syndrome. The first stage of the approach employs a substring search for two binding grooves of WW domains and possible binding motifs of peptide ligands based on known features. The second stage aligns the ligand's peptide backbone to the two binding grooves using a quasi-Newton constrained optimization algorithm. The backbone-aligned ligands produced serve as good starting points to the third stage which uses any flexible docking algorithm to perform the docking. The experimental results demonstrate that the backbone alignment method in the second stage performs better than conventional rigid superposition given two binding constraints. It is also shown that using the backbone-aligned ligands as initial configurations improves the flexible docking in the third stage. The presented approach can also be applied to other protein domains that involve binding of flexible ligand to two or more binding sites.

p63 threonine phosphorylation signals the interaction with the WW domain of the E3 ligase Itch

“…Subsequently, Autodockver 4.2 115 and AutodockVina version 1.1 algorithms 117 were used for the docking of TPPPY, T p PPPY peptides and their trans/cis proline to the Itch-WW domain. The binding of each peptide to the Itch-WW domain was performed by, using the docking procedure for rigid receptor and flexible or semiflexible ligand based on a knowledge guided Protein Docking as already reported by Lu et al 118 All the molecules were prepared for docking using Autodock Tools version1.4. 116 The default settings were used for all other parameters.…”