SONATA BIS

Understanding molecular mechanisms underlying the key cellular processes is a crucial challenge in biosciences. In these lines, studying interactions between the molecular participants of these processes is necessary to improve such an understanding. Molecular modeling tremendously advanced in its significance and applicability to tackle this challenge due to the dramatic development in computational technologies recently. This allows to use computational approaches not only to complement experimental studies but also to analyze molecular systems gaining principally new insights unfeasible for the experimental techniques. In this project, we are going to model biomolecular interactions in the extracellular matrix (ECM) with a focus on one of its major components, glycosaminoglycans (GAGs). GAGs represent a class of long linear anionic periodic polysaccharides made up of repetitive disaccharide units. Owned to the interactions with diverse proteins such as cytokines, growth factors, collagen, antithrombin, they are active participants in anticoagulation, proliferation, adhesion, cell signaling and immune mechanisms. As a consequence, GAGs were shown to be key players in a number of diseases associated with the pathologies of different tissue development as well as inflammatory/autoimmune disorders, cancer, prion and Alzheimer’s diseases. This renders GAGs to be very promising targets for the design of novel biomaterials to selectively control and promote the processes for potential medical applications in the field of bone and skin regeneration. However, often molecular mechanisms underlying GAG-mediated processes in the ECM are not fully elucidated, and application of experimental techniques is not sufficient alone for characterization of the interactions occurring at molecular levels. Therefore, theoretical approaches beneficially contribute to the understanding of the role of GAGs by bringing principally new and experimentally inaccessible details. Despite substantial success of the recent studies aimed to model GAG-mediated interactions, computational approaches still experience challenges due to GAGs high flexibility, long chains, symmetry, periodicity as well as their anionic nature rendering a requirement for rigorous solvent and electrostatic treatment. It is still not clear if protein/peptide-GAG recognition is predominantly electrostatically driven or specific. In our work, we plan to address the mentioned challenges. In these lines, we are going to reveal the function of GAGs in biologically relevant systems in terms of their impact on protein conformational properties and enhancement of protein-ligand interactions. To achieve the goal, we specify several tasks to accomplish: i) characterization of GAG interactions with particular protein targets as integrins, anastellin, cathepsin proteases, sclerostin; ii) characterization of GAG interactions with biologically active small molecules; iii) analysis of the impact of different ions on GAG structure and GAG-mediated interactions; iv) analysis of the GAG effect on peptides structuring; v) creation of coarse-grained parameters for GAGs to model multicomponent molecular complexes and systems with high conformational flexibility; vi) further development of computational methodologies specifically for the GAG containing systems.