The research could lead to better drugs and new tools in synthetic biology

Proteins are the engines of life, powering processes such as muscle movement, vision and chemical reactions. Their environment—water, lipid membranes, or other condensed phases—is critical to their function, shaping their structure and interactions.

However, many modern protein design methods, including AI-based tools, often ignore how these environments affect proteins. This gap limits our ability to create proteins with new functions, slowing advances in medicine and biotechnology.

One group of proteins that work in such specialized environments are membrane receptors, which act as biological “antennas”, detecting signals from the environment and eliciting cellular responses.

Among proteins, 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 often mediated by water. These collectively allow GPCRs to change shape and communicate the signals they receive into the cell.

So critical are these molecular gates to normal cellular function that around a third of all drugs on the market target them. However, GPCRs are also at the forefront of protein engineering, with efforts being made to modify these receptors to enhance drug efficacy, develop new disease treatments, and even repurpose them as bioaccumulators in synthetic biology.

The catch? GPCRs are incredibly complex, and their delicate dependence on water for function has been impossible to logically design—until now.

A team of scientists led by Patrick Barth at EPFL has developed advanced computational tools aimed at shifting the scales of GPCRS water-mediated interactions to design new membrane receptors that outperform their natural counterparts. Their work, now published in Nature chemistrycould lead to better drugs and new tools in synthetic biology.

Water is everywhere. It is the unsung hero of protein function, but is often overlooked in design, particularly when considering the allosteric membrane receptor, because it is difficult to model explicitly. We wanted to develop a method that can design new sequences while thinking about the effect of water on these complex hydrogen-bonding networks that are so critical for mediating signals in the cell.”

Lucas Rudden, Research Associate

At the heart of the effort is a computational design tool called Spades. The researchers used it to create synthetic GPCRs. Starting with the adenosine A2A receptor as a model. They focused on modifying “hubs,” key points of interaction between water molecules and amino acids. These nodes act like switchboards, relaying information throughout the protein. By designing networks that optimize water-mediated connections, the team generated 14 new receptor variants.

Spades software allowed them to simulate how these changes would affect receptor shapes and functions in different critical situations. After computational screening, the team then identified the most promising receptors and examined their activities in cells.

What they found was remarkable: the density of water-mediated interactions turned out to be a key determinant of receptor activity. Receptors with more of these interactions showed higher signaling stability and efficiency. The most promising design, called hyd_high7, even adopted an unexpected and unpredictable shape, validating the design models.

The 14 new receptors outperformed their natural counterparts in several ways, including their ability to remain stable at high temperatures and their enhanced ability to bind signaling molecules. These properties make them not only functionally superior but also more powerful for use in drug discovery and synthetic biology.

The project has enormous potential for medicine and biotechnology. By enabling the precise engineering of membrane receptors, the new method could lead to better targeted therapies for diseases such as cancer and neurological disorders. Beyond medicine, these synthetic receptors could be used in biosensors or other tools to detect environmental changes.

The findings also challenge long-held assumptions about how GPCRs work, revealing an unexpected flexibility in water-induced interaction networks. This opens new avenues to explore an untapped potential of these proteins both in nature and in the laboratory.

Other contributors

• Baylor College of Medicine
• Lilly San Diego Biotechnology Center
• Lilly Research Laboratories