How phosphorylation affects peptide interaction with adaptor domains

• Applicant: Professor Dr. Volkhard Helms
• Subject Area: Biophysics ; Bioinformatics and Theoretical Biology
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 392219411

Protein-protein interactions (PPIs) are of fundamental relevance for most processes in biological cells and hence the focus of considerable experimental and computational efforts. Notably, PPIs may also be strongly affected by post-translational modifications of the involved proteins such as phosphorylation that may either favor or disfavor formation of a particular complex. In this project, we will analyze interactions of adaptor domains with phosphorylated and unphosphorylated peptide binders by means of molecular dynamics simulations. We will build on the successful characterization of such binding processes in a first funding phase, where we studied binding of phospho/non-phospho peptides to the PDZ2 domain of the hPTP1E protein and to the PDZ1 domain of the MAGI1 protein by comparable simulations. In this project, we will at first correct slight inaccuracies of the phosphate parameters by calibration against experimental binding affinities. In collaboration with a structural biology group, we aim at establishing a mechanistic description why phosphorylated amino acids can either favor or disfavor binding of the peptide to PDZ domains depending on where the phosphate group is placed along the peptide sequence. These MD simulations will then be extended to MAP1LC3A ATG8 domains and TSG101 UEV domains. Finally, we will develop a classifier that can predict, for a given atomistic structure of a PDZ domain and for the sequence of a peptide binding to it, whether either its phosphorylated or non-phosphorylated variant binds more strongly, and a regression model for the difference in free binding enthalpy.

• DFG Programme: Research Grants