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Nov 24, 2023
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New Method Reveals Folding Speed Limit for Helical Membrane Proteins

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Membrane proteins

In the ever-evolving realm of molecular biology, understanding the intricacies of helical membrane proteins’ folding speed has long been a puzzle. Recent breakthroughs in methodologies have led to a novel approach, unveiling a previously hidden speed limit in this crucial biological process. Join us as we explore the cutting-edge method that promises to reshape our comprehension of helical membrane proteins.

Helical membrane proteins are essential in cellular functions, acting as gatekeepers and transporters across cell membranes. The complexity and precision with which these proteins fold determines their functionality. The quest to determine the speed limit of this folding has been an ongoing challenge. Enter the revolutionary new method for shedding light on this biological mystery.

Membrane proteins play key roles in various cellular functions and are key targets for drug intervention. Approximately 60 percent of the drugs currently on the market target these specific proteins. To develop effective drugs that interact with membrane proteins, it is essential to understand the structure of membrane proteins and the fundamentals of the folding process.

Recognizing this urgent need, Prof. Duyoung Min and his research team at UNIST’s Department of Chemistry embarked on a pioneering study to reveal the folding dynamics of helical membrane proteins. By developing a robust single-molecule tweezers approach using dibenzo cyclo cycloaddition and streptavidin binding, the team succeeded in estimating the folding “speed limit” of these proteins. These findings provide valuable insights into structural states, dynamics, and energy barrier properties and are critical to advancing our understanding of this field.

Single-molecule tweezers, including magnetic tweezers, have emerged as powerful tools for studying nanoscale structural changes of individual membrane proteins under force. However, previous studies were limited by weak molecular chains due to force-induced bond scission, preventing long-term observations of repeat molecular transfer. Overcoming this challenge is critical to obtaining reliable characterizations of structural states and dynamics.

In their study, published in the May 2023 issue of the journal eLife, Prof. Min and his research team introduced an innovative single-molecule tweezer approach that exhibited superior stability compared to conventional linkage systems. The lifetime of this new method is more than 100 times longer than that of existing methods, surviving for 12 hours at forces up to 50 pn and allowing approximately 1000 pull cycle experiments.

Using this advanced technique, the research team observed many structural transitions within the engineered single-chain transmembrane dimer under a constant force of 12 pN for 9 hours. These observations provide unprecedented insight into its folding pathway and reveal previously hidden dynamics associated with helical-coil switching.

To accurately characterize the energy barrier heights and folding times during these transitions, the researchers employed a model-independent deconvolution approach combined with Hidden Markov Modeling analysis. Results obtained using the Kramers rate framework revealed a very low-speed limit of 21 ms for helical hairpin formation in lipid bilayers, in contrast to the typical microsecond scale of soluble protein folding. This difference can be attributed to the high viscosity of lipid membranes, which hinders helix-helix interactions.

These findings provide more effective guidance for understanding the kinetics and free energy associated with membrane protein folding, which is a key factor in the development of drugs targeting membrane proteins. Since approximately 60 percent of drugs on the market focus on these proteins, this research opens new avenues to enhance drug research and design.

In conclusion, the discovery of a folding speed limit for helical membrane proteins marks a paradigm shift in molecular biology. This innovative method not only provides a new lens to observe protein folding but also opens doors to transformative applications in drug development and collaborative research. As we delve deeper into the microscopic realm, the horizons of biological understanding continue to expand.

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