DNA nanotechnology

Overview of modeling activities in DNA nanotechnologyDNA nanotechnology is a rapidly growing field of science that holds great promise for creating nanodevices capable of programmable transport and delivery of molecular cargoes, high-precision molecular sensing, nanomanufacturing, molecular computing, and countless other applications. However, for these applications to become a reality, the devices need to be rapidly actuated, precisely assembled into macroscopic arrays, and interfaced with inorganic and biological systems. Our lab uses theory and computations, often in close collaboration with experimentalists, to address many of these challenges. We use methods grounded in statistical physics to account for thermal fluctuations and treat the devices at different resolutions to address their dynamics at various scales ranging from base pairing interactions to conformational transitions to mesoscopic diffusion and self-assembly (Fig. 1).

Equilibrium angles and the size of their fluctuations obtained from modeling versus experimentsOne of our first projects was on testing the ability of the recently developed oxDNA coarse-grained model to predict the conformational dynamics of compliant DNA devices. We used the set of tunable DNA origami hinges designed by the Castro group (Ohio State) as our model system and showed that oxDNA could accurately reproduce the experimentally measured bending angles and their fluctuations for a range of hinge designs (Fig. 2). Our simulations also revealed new insights into the stability of the hybridized portions of the hinges, conformations of their single- and double-stranded components, and their global motions and bending mechanisms, properties that are challenging to obtain experimentally. We also introduced a novel approach for rapidly predicting hinges angles based on force-deformation characteristics of their components (Fig. 3). Ongoing efforts are attempting to generalize this approach to other structural designs.

A force-balance approach for rapidly predicting hinge equilibrium anglesOver the past couple of years, we have been working in close collaboration with the Castro group on developing a new rapid and noninvasive strategy for actuating DNA nanodevices. Our approach involves introducing multiple, weakly complementary pairs of single-stranded DNA overhangs to components of the structure and triggering hybridization or dissociation of the overhangs via changes in solution ionic conditions to drive structural transitions. We developed a simple statistical-mechanical model to explain and fit the actuation responses obtained experimentally. We are currently developing a novel free-energy decomposition strategy for computing the free energy landscape associated with the actuation transition, an otherwise computationally prohibitive task (Fig. 4). In addition to establishing a rigorous thermodynamic basis of actuation, this will also allow “ab-initio” predictions of actuation responses and help us develop simple design rules for tuning the actuation behavior.

Figure 4: Decomposition of the overall free energy of the hinge into contributions from the bare hinge and overhang pairs.Moving forward, we aim to use these tailored computational tools to design smart, dynamic DNA devices for sensing osmotic, compressive, extension, and shear forces. We would also like to develop strategies for assembling 1D and 2D arrays of such devices for communicating the sensed signals and magnifying the response by triggering collective behaviors like phase transitions. Another important application that we are working towards is targeting, visualizing, and engineering chromatin. Both these projects are in close collaboration with the Castro and Poirier groups (Ohio State), with the Lakadamyali and Tora groups  also bein involved in the chromatin project. Lastly, we have initiated new collaborations with Dr. Yonggang Ke (Georgia Tech/Emory), Dr. Tao Ye (UC Merced), and Dr. Ashwin Gopinath (MIT) on the assembly and orthogonal placement of DNA tiles on surfaces.