Research can lead to better drugs and new tools in synthetic biology

Proteins are life engines that drive processes such as muscle movement, vision and chemical reactions. Their lipid circles or other condensed phases-critical for their functions, shaping their structure and interactions.

However, many modern protein design methods, including tools based on artificial intelligence, often ignore the way this environment affect proteins. This gap limits our ability to create proteins with new functions, slowing down progress in medicine and bioengineering.

One of the groups of proteins operating in such specialized environments are membrane receptors that act as biological “antennas”, detecting signals from the environment and causing cellular answers.

Among the proteins, receptors coupled with G (GPCR) protein are of key importance for sensing cells and responding to external stimuli. To signal, GPCR is based on a delicate mutual relationship between structural stability, flexibility and binding of a legand, balancing files that often mediate water. They allow a joint GPCR to switch shape and communicate signals that they receive to the cell.

The key are molecular gardeepers for the normal cell function that about one third of all drugs on the market are addressed to them. But GPCR is also in the foreground of protein engineering, and efforts made to improve these receptors to increase the drug effectivenessDevelop new methods of treating the disease, and even for the purpose of their purpose as bio -signs in synthetic biology.

Hook? GPCR is extremely complex, and their gentle rely on the water for the function was impossible for a rationally engineer – so far.

A team of scientists under the leadership of Patrick Barth from EPFL has developed advanced computing tools that are aimed at moving the scale of interaction via GPCR to design new membrane receptors that exceed their natural counterparts. Their work, currently published, can lead to better drugs and new tools in synthetic biology.

Water is everywhere. He is an unknown hero of the protein function, but he is often ignored in design, especially when we look at the receptor of the Alloster membrane, because it is difficult to openly model. We wanted to develop a method that can design new sequences, thinking about the impact of water in these complex hydrogen bond networks, which are so crucial for mediation of signals in the cell. “

Lucas Rudden, author of studies

The heart of the effort is a computing design tool called Spades. Scientists used it to create synthetic GPCR. Starting from the A2A adenosine receptor as a template. They focused on the modification of “communication nodes”, key places of interaction between water molecules and amino acids. These hubs act as switchgear, providing information throughout the protein. When designing networks that optimize connections via water, the team created 14 new receptor variants.

PIK software allowed them to simulate the way these changes will affect the shapes and functions of receptors in various critical states. After computing screenings, the team synthesized the most promising receptors and tested their cell activity.

What they found was unusual: the density of interaction through water turned out to be a key indicator of receptor’s activity. Receptors with more of these interactions showed higher stability and signaling effectiveness. The most promising project, called HYD_HIGH7, even adopted an unexpected and unforeseen shape, confirming design models.

14 new receptors exceeded their natural counterparts in several ways, including their ability to remain stable at high temperatures and their increased ability to bind signal molecules. These features make not only functionally better, but also more solid for use in discovering synthetic drugs and biology.

Work has great potential in the field of medicine and biotechnology. By enabling precise membrane receptors engineering, the new method can lead to better targeted therapy of diseases such as cancer and neurological disorders. In addition to medicine, these synthetic receptors can be used in biochets or other tools for detecting environmental changes.

Discoveries also question long assumptions about GPCR, revealing unexpected flexibility in their interaction networks through water. This opens up new opportunities to examine the unused potential of these proteins in both nature and the laboratory.

Other colleagues

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