The Conformational Dynamics of Transmembrane Rotaxanes Revealed
Lead Research Organisation:
University of Reading
Department Name: Chemistry
Abstract
Conformational change underpins the existence of every living thing. In biology, proteins in cell membranes change their conformations to catalyse reactions, transfer information across the membrane, and generate membrane potentials. Every change in conformation is associated with a set of conformational dynamics, which are kinetic and thermodynamic parameters that dictate how a protein operates. Embedding proteins in lipid membranes enables them to facilitate communication between otherwise incompatible cellular compartments and generate energy gradients, which are required for the synthesis of high energy molecules (like ATP). Synthetic molecules that insert into lipid membranes and use conformational change to perform tasks are highly valued commodities. Such molecules could replace defective proteins, release drugs on demand from artificial cells, or be incorporated into novel, compartmentalised materials to enable them to breakdown and recycle chemical feedstocks and harness energy gradients in a manner akin to biological tissue.
Rotaxanes are molecules that comprise a macrocycle encircling a linear thread. Rotaxanes exhibit conformational change when the macrocycle moves along the thread, between recognition sites. This motion has been used to perform tasks such as catalysis, molecular transport, and the generation of nonequilibrium conditions. These behaviours suggest that rotaxanes could act as "artificial membrane proteins", which could be used to interface with biology or be components in materials with emergent "life-like" properties. However, although rotaxanes can perform these tasks in solution, there are limited examples of them operating in lipid membranes, which limits the utility of rotaxane-based nanotechnology. This lack of progress is likely because the conformational dynamics of rotaxanes in lipid membranes are unknown. Once a fundamental understanding of rotaxane conformational dynamics in lipid membranes has been obtained, the behaviour of rotaxanes in membranes can be optimised, allowing them to compete with biological membrane proteins, which operate with exquisite levels of precision, accuracy, and control. The aim of this research project is to obtain a fundamental understanding of the conformational dynamics of rotaxanes in lipid membranes, for the first time.
This ambitious research project will involve the synthesis of a series of rotaxanes, which will be inserted into lipid membranes and their conformational dynamics studied using powerful spectroscopic techniques. Each rotaxane synthesised will possess a different type of interaction between its macrocycle and the recognition sites on the thread, which will enable us to conduct a comprehensive investigation into how subtle differences in rotaxane structure affect conformational dynamics in the lipid membrane. We will also vary the composition of the lipid membrane, enabling us to determine how the structure and fluidity of the membrane perturbs rotaxane conformational dynamics.
Our results will transform the understanding of how rotaxanes behave in lipid membranes, paving the way for these molecules to be used for advanced transmembrane applications, such as the generation of energy gradients or harnessing gradients to drive secondary processes, such as catalysis. In the long-term, the fundamental insights provided by this proposal will enable rotaxanes to be embedded in lipid membranes, allowing them to interface with cells (for drug delivery, or to short-circuit biochemical pathways), or be used to direct molecular manufacturing inside membrane-bound compartments. Our research will also enable rotaxanes to be embedded in compartmentalised materials that contain artificial self-assembled membranes, imbuing these materials with "life-like" properties, enabling them to harness and control energy, reconfigure themselves at the molecular and macroscopic level, and use chemical feedstocks with the same level of precision as biology.
Rotaxanes are molecules that comprise a macrocycle encircling a linear thread. Rotaxanes exhibit conformational change when the macrocycle moves along the thread, between recognition sites. This motion has been used to perform tasks such as catalysis, molecular transport, and the generation of nonequilibrium conditions. These behaviours suggest that rotaxanes could act as "artificial membrane proteins", which could be used to interface with biology or be components in materials with emergent "life-like" properties. However, although rotaxanes can perform these tasks in solution, there are limited examples of them operating in lipid membranes, which limits the utility of rotaxane-based nanotechnology. This lack of progress is likely because the conformational dynamics of rotaxanes in lipid membranes are unknown. Once a fundamental understanding of rotaxane conformational dynamics in lipid membranes has been obtained, the behaviour of rotaxanes in membranes can be optimised, allowing them to compete with biological membrane proteins, which operate with exquisite levels of precision, accuracy, and control. The aim of this research project is to obtain a fundamental understanding of the conformational dynamics of rotaxanes in lipid membranes, for the first time.
This ambitious research project will involve the synthesis of a series of rotaxanes, which will be inserted into lipid membranes and their conformational dynamics studied using powerful spectroscopic techniques. Each rotaxane synthesised will possess a different type of interaction between its macrocycle and the recognition sites on the thread, which will enable us to conduct a comprehensive investigation into how subtle differences in rotaxane structure affect conformational dynamics in the lipid membrane. We will also vary the composition of the lipid membrane, enabling us to determine how the structure and fluidity of the membrane perturbs rotaxane conformational dynamics.
Our results will transform the understanding of how rotaxanes behave in lipid membranes, paving the way for these molecules to be used for advanced transmembrane applications, such as the generation of energy gradients or harnessing gradients to drive secondary processes, such as catalysis. In the long-term, the fundamental insights provided by this proposal will enable rotaxanes to be embedded in lipid membranes, allowing them to interface with cells (for drug delivery, or to short-circuit biochemical pathways), or be used to direct molecular manufacturing inside membrane-bound compartments. Our research will also enable rotaxanes to be embedded in compartmentalised materials that contain artificial self-assembled membranes, imbuing these materials with "life-like" properties, enabling them to harness and control energy, reconfigure themselves at the molecular and macroscopic level, and use chemical feedstocks with the same level of precision as biology.
