Towards a molecular supermarket

Proteins have many vital functions and can act as a structural element, a messenger substance, or a transporter. Their properties are largely determined by the architecture formed by their building blocks when they join together. Alena Khmelinskaia studies the physical methods through which proteins self-organize into three-dimensional structures — and designs brand-new proteins with properties that are tailormade for biomedical or other applications.

Growing up in Portugal, Khmelinskaia originally wanted to be a pianist. “But my parents didn’t think that was a very easy career path,” she explains, “so I started a degree in biochemistry in Lisbon.” During her studies, she discovered her love of biophysics when, purely by chance, she was given the opportunity to do some research in a lab specializing in membrane biophysics. Even after that, coincidences or “lucky mistakes,” as she calls them, have repeatedly played a fruitful role in her professional career. “And sometimes I’m just stubborn and, when I really want to do something, I won’t stop until I make it happen,” she says.

Her interest in membrane biophysics eventually led her to Munich, where she worked as a researcher at the Max Planck Institute of Biochemistry and obtained her doctorate in physics at LMU. Khmelinskaia was then keen to work in synthetic biology and protein design and moved to the University of Washington in Seattle (USA) to do that, before eventually building her own research group at the University of Bonn.

Computer modeling and lab experiments

Since April 2023, Alena Khmelinskaia has been back in Munich, where she is Professor of Biophysics at LMU. Her research combines computer-aided protein design with lab experiments in which she and her team synthesize and biochemically characterize the proteins that the computer algorithms develop. “We want to see if we’ve solved the design challenge,” says Khmelinskaia, “and it’s just satisfying to know that the protein actually works.”

Although she sees herself fundamentally as a basic scientist, she always keeps an eye on possible applications for her designs: “It’s very motivating to be producing materials that are more useful than the ones currently available.” She describes one of the architectures she’s working on as a kind of a protein ball on a very small scale. “The outside of this ball can be ‘decorated’ with certain molecules so that it interacts with its surroundings. But you could also enclose substances inside it if you needed to deliver them to a target.”

Tailormade solutions

To date, artificially designed proteins have essentially been based on rigid building blocks that obey strict rules of symmetry. The classic shape is an icosahedron, which is also found in the architecture of many virus capsids. If a certain ‘cargo’ needs to be transported using such a designer capsid, a new capsid currently has to be created for each different size of cargo. The release of the cargo is also often a challenge, given the “brick”-like nature of these cargos.

Khmelinskaia’s goal is to make this system more versatile by including flexible protein components and dynamic contacts. The aim here is to generate a greater variety of forms and functions so that proteins can be tailored to meet specific requirements. “In the best-case scenario, this would allow us to create something like a supermarket for protein balls based on a universal platform, where a scientist could order the exact specifications they needed.”

In one of her current projects, her team is working on designing materials with controlled porosity. “We are trying to produce materials that start out with a lower porosity but which semi-dissolve and thus become more porous as the pH value changes,” says Khmelinskaia. To do this, they create structures consisting of two interlocking polyhedrons that break down into two separate polyhedrons when the pH changes. “It’s a type of assembly we came across by chance,” says Khmelinskaia, “and it turned out to be a very exciting challenge because it’s mathematically interesting how the shapes have to fit together and also how can such an assembly form in real life.”

Khmelinskaia is sure that protein design will continue to gain importance as time goes by. Many things that were not previously possible are now within reach, according to the biophysicist, and the applications could go beyond biological systems. When it comes to her future work, she particularly appreciates the inspiring scientific environment she has around her in Munich, where there is a huge amount of expertise in biophysics, materials science, and synthetic biology: “It’s nice to be in a place where people vibrate at the same frequencies and where it’s really easy to exchange ideas on a scientific level. It’s been fantastic so far, and I’m really looking forward to what’s to come.”