The low contrast of biomolecules in TEM has been a great obstacle for their structure determination and hence to the understanding of their structure-function relation. Historically, single DNA strands remained one the most difficult classes of biomolecular specimens to image, due to low electron scattering strength of its constituent elements. The common practice was then to image them either when freely suspended (without any support) or shadow image them with negative staining technique. Those remedies are limited in terms of applicability to different DNA nanostructures as well as pose difficulties in sample preparation. For example, making the 2D DNA nanostructures freestanding would not be a viable solution for imaging them. This thesis provides a general study to tackle the challenges in imaging nucleic acids with TEM.

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