Metadynamics and Free-Energy Landscape Approaches for Structural Characterization of Galectin-3

The study addresses the three-dimensional structure and folding dynamics of Galectin-3 through the use of in-silico techniques like as DeepMind's AlphaFold, homology modelling, and ab-initio methods. The structural validation of the modelled structures highly supports the AlphaFold model. The N-terminal intrinsically disordered region a particular phenomenon frequently connected to the intrinsically disordered sections of proteins and its unexplored role in liquid-liquid phase separation are highlighted. The protein's metastable states were investigated using free energy landscaping, and the metastable state with the lowest global energy minima was the focus of in-depth dynamics studies. This gave researchers a thorough understanding of the structural flexibility of the Galectin-3 protein and the main factors influencing its coordinated movements. GoldScore and ChemScore are the best scoring functions, according to enrichment analysis, for determining candidate Galectin-3 carbohydrate-binding activity inhibitors. The FDA-approved compound ceftaroline shows high affinity and favourable interactions with the refined complete structure of Galectin-3, according to a newly introduced weighted scoring function that takes into account both GoldScore and ChemScore metrics. Ceftaroline was subjected to 100 ns molecular dynamic (MD) simulations, and the ceftaroline-Galectin-3 complex was found to be stable. This computational work sheds light on the structural dynamics of galectin-3 and lays the groundwork for upcoming experimental confirmations and medical advancements.