Scientists unlock new patterns of protein behavior in cell membranes

The cellular membrane proteins play many important roles throughout the body, in particular by transporting substances in and outside the cell, by transmitting signals, accelerating reactions and helping neighboring cells to stay together. Their dysfunction can cause serious illnesses, especially cancer, which makes them attractive therapeutic targets. But understanding how membrane proteins behave and operating can be difficult, because their position within the lipid membrane of the cell (a tight double layer of molecules resembling fat) makes them difficult to study.

Today, Scripps Research scientists have developed a new computer strategy to understand the functioning of these proteins at the atomic level. Posted on October 7, 2025 in PnasThe team designed synthetic membrane proteins that are easier to study in the laboratory, while revealing the structural base on which some keep their shape. Scientists can use this method to design new drugs, biotechnologies and therapies targeting membrane proteins directly.

“Billions and billions of dollars are devoted each year to the manufacture of molecules that target membrane proteins to modify their behavior and fight diseases, but to modulate these proteins, it is useful to understand first how they work,” explains the main author Marco Mravic, assistant professor in the Department of Structural and Integrative Computational SCripPS. “Our study has revealed new rules of sequence and atomic arrangements within membrane proteins which are essential to their functioning.”

The membrane proteins are made up of several folded proplored and closely tight propeller against each other, similar to the small strands intertwined with a rope. To maintain their complex architecture and function properly, the different parts of the protein must bind to each other than to the lipid membrane in which they are integrated.

The Mravic team wanted to understand the role of a common model or “motif” which appears in many different types of membrane proteins: a small amino acid which repeats all seven amino acids in protein chains when they cross the lipid membrane of the cell. This model means that these small amino acids are present in the same position each turn on two of a given propeller.

They hypothesized that these reasons represent potential “tights” points that help membrane protein propellers to bind to each other and organize within their membrane folds. To understand why this reason is so preserved and how atoms create stability, the researchers used a computer program to design what they thought to be idealized versions of the motive to study in the laboratory.

“It is generally very difficult to study the behavior of membrane proteins in our body, because as soon as we extract them from the cell, they want to disintegrate,” explains Mravic. “Our approach is unique insofar as we conceive of new synthetic proteins from zero with computer programs to get closer to the behaviors and atomic structures of membrane proteins of nature. We can use these design proteins as models to ask questions and clarify the rules underlying many complex processes occurring in cell membranes that we could not see or study otherwise.”

The first author, Kiana Golden, wrote software to identify the amino acid sequences containing this pattern and used this information to design synthetic membrane proteins optimized with improved stability. When the researchers produced these synthetic proteins in the laboratory, the proteins fell aside, consolidating the hypothesis that these reasons create “sticky points” between the adjacent propellers which maintain membrane proteins together in lipids.

Likewise, Golden has shown that when the reasons received the most optimal sequences, this led to extremely stable synthetic proteins, and even remained intact in boiling conditions.

“We discovered that the stability of the pattern was due to an unusual type of hydrogen bond, generally very low, but when the pattern is repeated, these low hydrogen links add up to form a very stable interaction,” explains Golden, who worked on the project as a first cycle student at the UCSD and is now a graduate student at the Princeton University. “This type of hydrogen link is rare in the natural world, so it was really surprising that it was largely what causes the appearance of this motif, and that biology has evolved to use it in specific patterns and structures through nature.”

Now that they have shown how this reason contributes to the structure of membrane proteins, researchers say that this information will help scientists and doctors to identify and understand the genetic mutations that could contribute to the disease. Since their team has proven that their new software could build very powerful protein complexes in lipids, they are now working on the design of molecules targeting the membrane proteins of the cell directly.

“Our approach considerably accelerates what we can discover about the internal functioning of membrane proteins and on how to develop better therapies,” explains Mravic.

In addition to Mravic and Golden, the authors of the study entitled “Principles of conception of the common constitutive block of the gly-X6-X6-Gly membrane protein” are Catalina Avarvarei, Charlie T. Anderson, Matthew Holcomb, Weiyi Tang, Xiaoping Dai Minghao Zhang, Colleen A. Mailie, Brittany B. Sanchez, Jason S. Stefano forli of scripps. Research.