This project focuses on developing and applying computational approaches to study GAG-protein interactions in order to better understand their requirements for affinity and specificity and to characterize the molecular mechanisms responsible for their function. We use the knowledge acquired to stablish structure-function relationships theoretical models and to propose rationale for customized specificity in order to guide the engineering of new biomaterials and thus be able to tune the interplay GAG/target-protein/receptor for functional purposes.

A great part of our work consists on applying computational tools in cooperation with experimentalists to investigate the interaction of a variety of GAGs with extracellular matrix target protein systems. We establish theoretical models for the analysis of the conformational properties of GAG derivatives, the location of their binding sites, the characterization of relevant target protein residues, as well as the interplay with their receptors. This integrative endeavour strengths the predictive value of our theoretical models, notably assists in the establishment of working hypothesis and their assessment, and advances our knowledge on GAG-protein molecular recognition and its functional implications in the investigated systems. Noteworthy results of our work are, for instance, the obtained new structural and functional insights into GAG-sclerostin interactions in bone (together with project B2) and into the molecular mechanism used by sulfated GAGs to exploit BMP-2 conformational plasticity (Fig. 1) and alter its receptor interactions (together with project A3).

We also develop computational methodology for the prediction and study of GAG-protein interactions. For instance, we have established a new molecular dynamics (MD)-based approach for molecular docking (DMD; Fig. 2), which takes GAG flexibility and explicit solvent into account and is optimized for GPU technology for intensive calculations. This method has allowed the characterization of GAG derivatives binding to a diverse collection of extracellular matrix proteins (Fig. 3-4).

Our studies will help in the design of building blocks for chemical and modular synthesis of GAGs-derivatives and matrix scaffolds in biomaterials to promote bio-specific cell behaviour.