Mechanistic Insights into the Specificity of Glycosaminoglycan Interactions withRegulatory Proteins

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In the project, we plan to study the specificity of the interaction between glycosaminoglycans (GAG) with regulatory proteins in a quantitative fashion. In particular, we will work on the question whether or not the recognition of GAG by proteins is characterized just by an unspecific electrostatics or by a pattern of highly specific interactions, such as salt bridges and hydrogen bonds. We plan to study in detail the interaction between interleukin-8, a common regulatory protein, with a number of negatively charged molecules such as GAG, peptides, nucleic acids or polymers by a combination of experimental and theoretical methods. Experimentally, we will particularly apply NMR methods. Computationally, we will carry out docking studies and molecular dynamics simulations. In the second part of the project, we plan to study the interaction of cathepsins with GAG by means of both techniques. Cathepsin B is characterized by a high positive surface charge, such that the unspecific interaction with negatively charged molecules is to be expected. We plan to test if in addition to such unspecific interaction, also highly specific interactions give rise to high affine GAG binding to the protein. We will study the structure of the complex by experimental and computational tools. The experimental techniques will be carried out in Germany, while the computational studies will be carried by the Polish collaboration partner. The applicants have been engaged in a fruitful and successful collaboration for many years with several common publications.