Proteins are life's engines, powering processes like muscle movement, vision, and chemical reactions. Their environments—water, lipid membranes, or other condensed phases—are critical to their function, shaping their structure and interactions.
Yet many modern protein-design methods, including AI-based tools, often ignore how these surroundings influence proteins. This gap limits our ability to create proteins with new functions, slowing progress in medicine and bioengineering.
One group of proteins working in such specialized environments are the membrane receptors, which act like biological "antennas", sensing signals from the environment and triggering cellular responses.
Among proteins, the G-protein-coupled receptors (GPCRs), are central to how cells sense and respond to external stimuli. To carry out their signaling, GPCRs rely on a delicate interplay between structural stability, flexibility, and ligand binding, balancing acts that are often mediated by water. These collectively allow GPCRs to switch shape and communicate the signals they receive into the cell.
So crucial are these molecular gatekeepers for normal cellular function that around one-third of all drugs on the market target them. But GPCRs are also at the forefront of protein engineering, with efforts made to tweak these receptors to boost drug efficacy, develop novel disease treatments, and even to repurpose them as biosensors in synthetic biology.
The catch? GPCRs are incredibly complex, and their delicate reliance on water for function has been impossible to rationally engineer — until now.
A team of scientists led by Patrick Barth at EPFL have developed advanced computational tools that aim to shift the scales of GPCRs water-mediated interactions to design new membrane receptors that outperform their natural counterparts. Their work, now published in Nature Chemistry, could lead to better medicines and new tools in synthetic biology.
