Inspired by the functionalities of natural macromolecules such as enzymes, molecular motors, and viruses, we investigate how to build increasingly complex molecular structures. The goal is to build molecular devices and machines that can execute user-defined tasks. Molecular self-assembly with DNA is one of the main routes currently pursued toward achieving this goal. In the long term we hope to contribute to the creation of molecular machines and systems with practical benefits for everyday life. This includes uses in medicine – for diagnosis and therapy – and synthetic enzymes for biologically inspired chemistry.
Creating molecular machines and motors that can work with efficiencies rivalling those of natural protein machines is an important unmet challenge. One obstacle toward realising such machines is the difficulty to build sufficiently sophisticated molecular structures. Another problem concerns incomplete understanding of the design principles for achieving the desired function. Exploring how to design increasingly sophisticated molecular structures is valuable, because it can yield an improved understanding of the links between sequence, shape, and function of biomolecules. Custom-designed macromolecular structures can also be employed as tools to support scientific discovery in various fields of research. Attempting to construct artificial molecular machines from biomolecules may enable an experimental test of models for the function principles of natural molecular machines. Artificial molecular machines and motors could help exploring how mechanical motion may be coupled to chemical reactions, and they may help to understand how increasingly complex enzymatic function can evolve from simple start mechanisms. But there is also a practical dimension: artificial molecular machines and motors could be used for example to drive chemical synthesis, to actively propel nanoscale drug delivery vehicles, to pump and separate molecules across barriers, or to package molecules into cargo components. We focus on DNA in particular as a programmable construction material to build nanometer-scale devices and mechanisms for applications in biomolecular physics, biological chemistry, and molecular medicine. 3D transmission electron microscopy and single molecule methods such as optical trapping and fluorescence microscopy are among our routine analysis tools.
Designing the sequences of biomolecules to construct increasingly sophisticated molecular devices and machines is the key interest of this laboratory. Our method of choice is 'scaffolded DNA origami' and we are striving towards improving this method in order to engineer ever more complex devices that achieve more sophisticated functionalities. We use a comprehensive approach that includes various types of physical / chemical modelling, detailed experimental studies of assembly behaviour and structure, and research on mass production to push DNA origami toward practical applications. We have also embarked in designing proteins for creating hybrid DNA-protein structures.
Life in a cell is dynamic: proteins zig-zag around, manufacture new molecules, chew up others, transport cargo, and read what's new on the daily DNA digest. Proteins are nanotechnological masterpieces brought upon by evolution with a missing user's manual. Watching such natural nanomachines in action provides valuable clues into how they actually work. To facilitate such studies, we develop custom nanometer-scale devices such as pliers or calipers using scaffolded DNA origami and attach these devices to target proteins in order to monitor and influence their dynamic behaviour. Conformational heterogeneity becomes measurable by transmission electron microscopy and/or in real-time using single-molecule fluorescence spectroscopy.
We develop methods for facilitating the structural analysis of biomolecules and their complexes. Our approach is two-fold: we are engineering and testing DNA-based alignment cages for 3D transmission electron microscopy to facilitate bottleneck steps such as cryogenic vitrification, image processing, and structural refinement. We also work on crystallographic approaches.
Our lab has direct access to high-end transmission electron cryo microscopy equipment, consisting of a 300kV FEI Titan Krios with direct electron detector and two 120kV-class TEM for sample screening purposes. For image processing we have access to a high-performance computing cluster.
DNA is a consistent surprise: with super-flexibility (1), negative twist-stretch coupling (2) and extreme extensibility (3), DNA has fascinating mechanical properties that are relevant for a range of biological processes such as transcriptional regulation or genomic packaging but also for people like us who use DNA for engineering. We aim to improve our understanding of DNA as a material for nanoconstruction by studying in detail its mechanical and dynamical properties, down to the level of interactions between single bases and single basepairs. Custom 3D DNA origami shapes in conjunction with single-molecule manipulation methods offer a rich playground for addressing these questions.