(477d) Enhanced Sampling on Human MUC2 to Study Interactions with Bile SALTS

Mucin 2 (MUC2) is the primary glycoprotein that forms the protective mucus barrier in the human intestine, playing a crucial role in maintaining gut homeostasis. However, its structural complexity—spanning over 5,200 amino acids, adopting an elongated conformation with an end-to-end distance of about 760 Å, and featuring extensive glycosylation in the Proline-Threonine-Serine (PTS) regions along with several disordered domains—makes MUC2 refractory to both experimental and computational studies. This presents a major challenge in understanding how MUC2 interacts with key signaling molecules in the intestine, such as bile salts. Investigating these interactions is critical to reveal how the mucus barrier regulates the transport and behavior of bile salts within the intestinal environment, and how such interactions may influence intestinal function and contribute to gut homeostasis.

In this study, we investigate the molecular interactions between MUC2 and sodium taurocholate (NATC), a major bile salt, using all-atom molecular dynamics (MD) simulations. We focus on how NATC binds to MUC2 and the resulting structural changes that occur upon binding. Through a strategic implementation of simulation windows along the length of the protein and the use of enhanced sampling techniques such as steered MD, we have identified key binding modes and examined how these interactions influence the conformation and stability of MUC2. These insights could contribute to improving therapeutic strategies and optimizing drug delivery systems that must navigate the intestinal mucus barrier.

This research offers a new perspective on the molecular mechanisms that govern the structure and behavior of the mucus barrier, particularly how bile salts modulate its integrity and function. To our knowledge, this is the first atomistic MD simulation performed on full-length MUC2. This work represents a significant step forward in modeling large, glycosylated proteins and introduces a new framework for studying glycoproteins at high resolution in complex biological environments.