Researchers at the University of Oxford have successfully observed virus-like particles assembling themselves one molecule at a time. The findings, published in Nature, reveal the surprisingly simple rules that allow complex biological structures to form with remarkable reliability. This direct observation of a process scientists have struggled to capture for decades offers new insights into how viruses construct their protective protein shells.
Tracking Molecular Construction
Understanding how viruses build their protective shells, known as capsids, is critical for developing new medical treatments. These shells consist of tens or even thousands of individual protein components that must organize themselves into the correct structure without any external machinery or blueprint. The Oxford team studied an engineered virus-like particle composed of 60 protein units to track this process in real time.
To overcome the challenge of capturing fleeting intermediate structures, the researchers used mass photometry. This technique, developed at Oxford, determines the mass of individual molecules by measuring the light they scatter. By combining this technology with a new method for keeping individual molecules confined and continuously observable, the team could repeatedly measure the mass of a growing particle as additional proteins attached. This approach allowed the scientists to follow the construction process as it happened, effectively tracking the addition of individual molecular building blocks over time.
Co-first author PhD student Dan Loewenthal described the method as taking a video of the assembly process. Co-lead author Professor Philipp Kukura noted that previous understanding had to be reconstructed from snapshots or theoretical models. Being able to quantify underlying interactions and follow one particle as it grows changes that dynamic. The team could see important intermediate structures appear and deduce a detailed model of the construction process.
Stable Checkpoints Guide Assembly
The study found that viral assembly resembles navigating a complicated maze where only certain paths lead to lasting progress. At first, protein components form weak connections that can easily break apart if the arrangement is unsuccessful. This flexibility allows the molecules to keep trying different combinations until they form particular closed structures. Once multiple connections hold these structures together, they become far more stable.
These stable arrangements serve as molecular checkpoints, narrowing the enormous number of possible assembly routes into a much smaller set of successful pathways. One especially important milestone occurs when five larger protein building blocks connect to form a closed pentagonal ring. This is the first highly stable structure in the assembly process. Once it forms, each subsequent stable stage requires fewer additional building blocks, allowing the particle to grow more quickly.
Dr. Roi Asor, co-lead author from the Department of Chemistry and Kavli Institute for Nanoscience Discovery, explained that a virus has to solve an extraordinary construction problem. Its components must find the right arrangement among a huge number of possibilities without a blueprint or machinery directing the process. The weak interactions give the system room to make mistakes. Most encounters do not have to be successful because the components can separate and try again. However, once enough of them come together in the right closed arrangement, the structure becomes stable, and assembly can move forward.
By identifying the molecular interactions that control viral assembly, scientists may eventually be able to develop treatments that interfere with the construction of viral protein shells. Co-author Dr. Jack Tan from the MRC Weatherall Institute of Molecular Medicine and CAMS-Oxford Institute noted that understanding these processes at the molecular level could have important applications in vaccine development and antivirals that disrupt viral assembly. The same insights could also support efforts to engineer virus-like particles for therapeutic applications.
Source: ScienceDaily
