Ultra-stable, high-bandwidth measurement platform for high-precision studies of rapid conformational dynamics in single biomolecules

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Biological molecules like proteins, DNA, and RNA form complex structures that are required for them to function correctly. Understanding how these structures form (known as ‘folding’) is important for understanding both proper function and dysfunction (which may lead to disease). One of the most sensitive ways to study folding is to use laser tweezers to grab onto single molecules and unravel their structure by pulling them apart. This proposal will build an ultra-stable system for measuring the folding of single molecules, one that can observe very rapid (~1 μs) events with atomic-scale resolution over long periods of time (tens of minutes), providing the most precise measurements to date of real-time structural changes in these molecules. We will use it to study fundamental questions such as how folding works as a physical process and what determines the specific behaviour observed. More specifically, we will study the very shortest-lived events during folding, the elusive ‘transition states’ that act as bottlenecks in the process and therefore dominate the dynamics. The path taken through the transition states contains all the critical information about the mechanism of folding, but it is very hard to detect. We will measure these ‘transition paths’ not only to learn about the basic physical principles of folding, but also to understand how folding goes wrong: such misfolding is at the root of many incurable diseases, like Alzheimer’s and ALS, but the mechanisms that drive it at the molecular level remain poorly understood. Furthermore, we will use the new instrument to study still-unsolved biological processes like how viruses can alter the way the genetic code is read, which pose important scientific riddles but also have potential applications in medicine. Studies like these, making use of the incredible resolution and sensitivity of single-molecule probes, are one of the hottest frontiers in folding studies. We have right now a remarkable opportunity to make significant and lasting advances in a decades-old problem with relevance to biology, physics, chemistry, and medicine. Without this instrumentation, we will not be able to pursue such exciting science.