Conformational Dynamics of the Multivalent Targets

Abstract

Multivalency is a ubiquitous mechanism in nature involved in numerous biological processes such as recognition, adhesion, self-organization of matter and signal transduction. Multivalency can be defined as the binding of n-valent ligand to an m-valent receptor through non-covalent, strong, but reversible interactions. Recently, multivalency has been applied as a principle to design novel molecules with a potential to fight the different microbes. Therefore, the majority of the experimental and theoretical framework has been developed in the areas facilitating the ligand design, while its respective receptor is usually assumed to be somewhat rigid. However, this assumption does not always hold. Thus the primary focus of this thesis was to investigate the conformational behavior of three multivalent systems with computational methods and to correlate these findings with the outcomes of the complementary experiments. First, we investigated the carbohydrate uptake and release by a trivalent C-type lectin receptor Langerin, since the little was known about this mechanism. The carbohydrate recognition is dependent on the Ca2+ cofactor. We demonstrated that the Ca2+ binding to Langerin is pH-sensitive and under control of a robust allosteric network. Additionally, we showed that the conformational dynamics of Langerin comprised several events occurring at different timescales. Then, I focused on elucidating the conformational dynamics and its influence on the design and the potency of the trivalent sialosides to inhibit a viral protein Hemagglutinin. Last, I explored a bivalent recognition process on the example of a proline-rich peptide SmB2 and tandem-WW domains of a spliceosomal Formin Binding Protein 21. In this study, I reported a highly complex conformational dynamics of the apo receptor, shed light on its respective free energy landscape, proposed a scheme for determining a binding-competent structure and mod