Researchers have created a new computational approach that takes into account the role of water when designing membrane receptors that are both stable and effective in signaling. This advancement could greatly facilitate drug discovery and protein engineering.
Proteins serve as the driving force behind numerous biological processes, such as muscle contraction, vision, and various chemical reactions. The environments in which they exist—be it water, lipid membranes, or other condensed phases—are crucial to their functionality, influencing both their structure and interactions.
Unfortunately, many contemporary methods for protein design, including those powered by AI, often overlook the influence of these environments on proteins. This oversight hinders our ability to engineer proteins with new functionalities, which can slow down advancements in medicine and bioengineering.
Membrane receptors are a specific group of proteins that thrive in such specialized environments. They serve a role similar to biological “antennas,” detecting signals from outside the cell and initiating appropriate cellular responses.
Within the protein category, G-protein-coupled receptors (GPCRs) are vital for how cells perceive and react to external stimuli. Their signaling capabilities depend on a careful balance of structural stability, flexibility, and ligand binding—often mediated by water—which allows GPCRs to change shape and convey external signals into the cell.
These essential molecular gatekeepers are so crucial to normal cell function that approximately one-third of all available medications target them. Furthermore, GPCRs are at the cutting edge of protein engineering, with efforts underway to modify these receptors to enhance drug effectiveness, create new treatments for various diseases, and even to adapt them as biosensors within synthetic biology.
The challenge? GPCRs are highly intricate, and their significant dependence on water for optimal function has made engineering them effectively a daunting task—until now.
A research team led by Patrick Barth at EPFL has crafted sophisticated computational tools that aim to redefine the role of water in GPCR interactions, enabling the design of new membrane receptors that surpass their natural models. Their findings, recently published in Nature Chemistry, could lead to improved pharmaceuticals and innovative tools in synthetic biology.
“Water is ubiquitous,” comments Lucas Rudden, one of the study’s co-first authors. “It plays an essential, yet often overlooked, role in protein function. It’s particularly challenging to incorporate into receptor design, as modeling it explicitly is tough. We aimed to devise a method that could create new sequences while factoring in the influence of water within those intricate hydrogen bonding networks critical for signal transmission into the cell.”
Central to this initiative is a design tool known as SPaDES. The team utilized it to engineer synthetic GPCRs, starting with the adenosine A2A receptor as a base. They emphasized modifying its “communication hubs,” which are vital interaction points between water molecules and amino acids. These hubs function like switchboards, transmitting information throughout the protein. By developing networks that enhance water-linked interactions, the researchers generated 14 new variants of the receptor.
The SPaDES software enabled them to model the impact of these variations on the receptors’ shapes and functionalities in critical states. Following computational screening, the team synthesized the most promising variants and evaluated their performance in cellular environments.
The results were impressive. They discovered that the prevalence of water-linked interactions significantly influenced receptor activity. Receptors with a higher density of these interactions demonstrated greater stability and signaling efficiency. Notably, one of the designs, termed Hyd_high7, adopted an unexpected shape that confirmed the integrity of the design models.
These 14 novel receptors outperformed their natural counterparts in various aspects, such as maintaining stability at elevated temperatures and enhancing the binding capacity for signaling molecules. This not only makes them functionally superior but also more resilient for applications in drug discovery and synthetic biology.
The implications of this work are substantial for medicine and biotechnology. This new method allows for the precise engineering of membrane receptors, potentially leading to more targeted therapies for conditions like cancer and neurological disorders. Beyond health care, these synthetic receptors could find utility in biosensors or other technologies for monitoring environmental changes.
Moreover, these findings challenge long-entrenched beliefs about GPCR functionality, uncovering an unexpected flexibility in their water-mediated interaction networks. This discovery opens up exciting new pathways for investigating the previously unexplored potential of these proteins in both natural and laboratory settings.
