Osmolyte-Mediated Protein Stabilization: Unraveling Interactions Across Conformational Landscapes

The folding of proteins from their initial unfolded or denatured states into their native functional conformation, known as the on-pathway process, explores a funnel-shaped energy landscape. Evidence suggests the presence of intermediates within this landscape. At times, proteins may become trapped in non-native conformations, making it challenging for them to reach their native structure without substantial reorganizational events, a phenomenon known as the off-pathway process. Protein aggregation is now widely acknowledged as a crucial and fundamental aspect of protein energy landscapes. Osmolytes have emerged as sophisticated naturally occurring mechanisms for protein stabilization. This chapter aims to explore the fascinating realm of osmolyte-induced stabilization of protein aggregates, focusing particularly on their intricate interactions with protein folding native, intermediate, and denatured states. By elucidating the molecular mechanisms underlying osmolyte–protein interactions, this exploration aims to reveal the versatile strategies employed by osmolytes to maintain protein integrity across various conformational landscapes.