We develop novel scientific devices and methods for applications in biomolecular physics, biological chemistry, and molecular medicine. To this end, we currently focus on using DNA as a programmable construction material for building nanometer-scale scientific devices with atomically precise features. We also customize proteins and create and study hybrid DNA-protein complexes. 3D transmission electron microscopy, atomic force microscopy, and single molecule methods such as optical trapping and fluorescence microscopy are among our routine analysis tools. A few words on biomolecular nanotechnology and its benefits can be found here. Below we outline in more detail our current research directions. Did you check our published results?
By folding into intriguing molecular shapes, proteins are able to carry out all kind of wondrous functions in our cells. We seek to develop novel methods for the structural analysis of protein molecules. Our approach is two-fold: we aim to construct DNA-based alignment cages for 3D transmission electron microscopy to facilitate bottleneck steps such as cryogenic vitrification, image processing, and structural refinement. We also aim to establish a solution-based protein triangulation method based on multiple two-point distance measurements carried out with a high-throughput protein mutant expression system.
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 a protein in action provides valuable clues into how it actually works. We seek to build custom-made 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 in reconstituted in-vitro systems. Conformational heterogeneity will be assessed by transmission electron microscopy and/or in real-time using single-molecule fluorescence spectroscopy. Ideally, this will go hand in hand with our efforts in developing novel methods for structural analysis of proteins. Our target-of-the-moment are DNA binding proteins that are involved in transcriptional regulation.
DNA Materials Science
DNA is a consistent suprise: 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 seek a better understanding of the materials properties of DNA by studying in detail the mechanical strength of the sequence-dependent base-stacking interaction and by studying the propensity of target DNA sequences to bend. Custom 3D DNA origami shapes in conjunction with single-molecule manipulation methods offer a rich playground for addressing these questions.
DNA and Protein Engineering
Molecular self-assembly with DNA is the current workhorse of our research efforts. Our method of choice is 'scaffolded DNA origami' and we are striving towards improving this method in order to engineer higher quality devices with more sophisticated functionalities. Robotic automation to enable higher-throughput manufacturing as well as development of software for computer-aided engineering are on our to-do-list. Previously, we have also done some tiny steps towards using proteins as building material and we plan to expand more into protein design in the future.