Croucher scholar uses simulation to advance study of DNA nanotechnology
Scientists began by making two dimensional shapes but soon they were able to create complex 3D structures. DNA nanotechnology, which aims to create nanoscale machines that can work inside the human body, has made great advances since then. Nano-robots injected into the human blood stream to undertake intelligent therapeutic tasks now seem within reach.
In 2009, Danish researchers engineered a DNA box that could open to release drug molecules, and an intelligent locking mechanism on the lid that could detect cancer cells before opening and releasing its payload of targeted drugs.
If this DNA origami could be combined with sensors and circuits, it opened the door to a nanorobot made entirely from DNA. Using DNA origami as building blocks for nanoscale instruments became the basis of DNA nanotechnology.
This is the exciting field of research that Marco Wong Chak Kui (Croucher Scholarship 2019) entered as an undergraduate at the Chinese University of Hong Kong (CUHK), when he went on an overseas research internship at the Physical and Theoretical Chemistry Laboratory in the Department of Chemistry at the University of Oxford.
“That was a game changer — an opportunity to work with a leading team on a theoretical chemistry project,” said Wong.
The laboratory, headed by Prof Jonathan Doye, was focused on the mechanical properties of large DNA nanostructures, and how they can be used to apply or sense force. Doyle’s team explored how DNA origami can be used as building blocks for larger scale self-assembly.
“That was my first introduction to working on DNA origami, and it sparked my interest in the field,” said Wong who successfully applied for a Croucher Scholarship to pursue a DPhil with Doye, after graduating from CUHK in 2019.
Simulating Nano Objects
Now in his third year of DPhil studies at Oxford, Wong said that while much of the work in the field of DNA origami is experimental, his work and that of his lab colleagues is more theoretical. His focus is to simulate these nano scale objects and calculate the qualitative properties of these structures. As the structures being engineered become more complex, the role of simulation becomes more critical.
“In experiments you can’t get the required resolution from microscopy. We can see what can’t be seen in experiments, it informs and greatly assists experiments,” said Wong who added that while to construct a DNA nanodevice may take a week or two, the simulation will typically only take a day or two.
Wong was lead author on a recent paper on characterising the free-energy landscapes of DNA origamis.
The free energy landscape underlies the thermodynamics and kinetics of any molecular processes in solution, so understanding it is essential for any successful nano-engineering. The authors described how coarse-grained modelling, which aims at simulating the behaviour of complex systems using their coarse-grained representation, combined with umbrella sampling using distance-based order parameters, can be applied to compute the free-energy landscapes associated with mechanical deformations of large DNA nanostructures.
He was also invited to assist with an innovative nanotechnology design theory being developed by the University of New South Wales (UNSW). This explored how to control the length of self-assembling nanobots in the absence of a mould, or template. He was co-author of the subsequent collaborative paper published in November 2020.
At UNSW, researchers used biological molecules, like DNA, to build nanorobots using a process called molecular self-assembly, where tiny individual component parts build themselves into larger structures.
Building to Scale
The challenge with using self-assembly is working out how to programme the building blocks to build the desired structure, and getting them to stop when the structure is big enough.
For this project, the UNSW researchers implemented their design by synthesising DNA subunits, called PolyBricks. As happens in natural systems, the building blocks were each encoded with the master plans to self-assemble into pre-defined structures of set length.
The authors used a design principle known as strain accumulation to control the dimensions of their built structures and this was one of the key contributions of Wong.
“We helped them visualise the stress accumulation mechanism via simulation,” he said.
With each block added, strain energy accumulates between the PolyBricks, until ultimately the energy is too great for any more blocks to bind. This is the point at which the subunits will stop assembling.
The authors say this mechanism could be used to encode more complex shapes using self-assembly units.
Wong can foresee the engineering of larger origamis which are no longer limited to the size of the scaffold; that is the long strand which is limited by the size of the virus strand known as M13.
“Another exciting area of work being undertaken in Munich uses DNA origami to build a shell to encapsulate a virus. This has the potential to be a future anti-viral agent,” said Wong.
In these innovative applications and experiments coarse grain modelling undertaken by Wong and his colleagues will be used in simulations to reveal how these origamis might fit together.
Marco Wong Chak Kui graduated with a BSc in chemistry from The Chinese University Hong Kong (CUHK) in 2019. He was introduced to the principles of theoretical chemistry by Professor Steve Tse Ying-Lung, who encouraged him apply for an internship at the University of Oxford. It was during this internship at Oxford’s Department of Theoretical Chemistry under the supervision of Prof Jonathan Doye, that Wong was exposed to the theoretical components of DNA origami for the first time. He successfully applied for a Croucher Scholarship in 2019 to continue his DPhil studies there and is now pursuing his DPhil in Physical and Theoretical Chemistry. He is a recipient of the University of Oxford Croucher Scholarship and the Clarendon Scholarship and has published and co-authored several papers on the computational modelling of DNA nanotechnology. Through coarse-grained molecular dynamics (MD) simulations, he investigates the structural and thermodynamic properties of DNA origamis and nano engineered molecular structures.
To view Marco’s Croucher profile, please click here.