Unveiling the Role of Flexibility in Designer Proteins

Artificially designed proteins are typically built using strict symmetrical rules, allowing researchers to computationally predict their structures. However, exceptions exist—some computationally designed proteins exhibit unexpected structures or properties.

A research team led by Professor Alena Khmelinskaia (Ludwig-Maximilians-Universität München) and Professor Neil King (University of Washington) has identified the reason: certain proteins contain flexible regions that enable them to adopt multiple conformations. This discovery has important implications for the design of custom-built proteins.

The researchers examined three designer proteins that formed structures significantly different from those predicted. These proteins are initially created through the reaction of two or three base components, forming dimers or trimers. In theory, these units should then self-assemble into highly symmetrical shapes, such as octahedra or icosahedra. However, the experiments revealed a different reality: alongside the expected structures, a substantial number of particles were observed to be much larger or had adopted entirely different architectures.

Investigating Deviations in Protein Structure

“To understand the cause of these deviations, we characterized these three reactions in detail,” explained Professor Alena Khmelinskaia.

Using a combination of cryo-electron microscopy, mass spectrometry, mathematical modeling, AI-assisted computational methods, and simulations, the team pinpointed the underlying cause. Their findings revealed that these proteins possess small, flexible regions that do not remain rigid, allowing structural variation.

Remarkably, this flexibility does not lead to random polymorphism but instead results in a limited set of distinct structures—a phenomenon known as oligomorphism.

Implications for Protein Design

This behavior mirrors that of natural proteins found in viral shells or those involved in vesicle formation, which also exhibit variability in size and shape. Despite their differing dimensions and configurations, the three studied proteins behave similarly to these natural counterparts.

“The oligomorphism we observed presents exciting possibilities for developing adaptable proteins tailored for specific applications. The design principles outlined in this study could significantly advance the creation of customized protein nanomaterials,” said Professor Khmelinskaia.

These findings pave the way for more versatile protein engineering, offering new directions for applications in medicine, nanotechnology, and beyond.