CAREER: Engineering Nucleic Acid Devices

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The Pierce Lab at Caltech proposes a research program that combines theoretical, computationaland experimental components to advance the field of structural nucleic acid nanotechnology in developing rigorous and robust methods for encoding arbitrary mechanical function in nucleic acid sequences. Modeling and algorithm development projects will address key analysis and design challenges. The investigation of pseudoknot biophysics will help to create a physically based potential for partition function algorithms and illuminate the role of topology in the behavior of the "kissing hairpin" mechanism under experimental study for catalytic fuel delivery to autonomous devices as well as:-on implementing an efficient hierarchical mutation algorithm for optimizing affinity and specificity for target secondary structures using partition function information-on methods for identifying and designing multiple features of an energy landscape including networks of metastable states relevant to autonomous device design-and on formulating and optimizing the multi-objective design problem that characterizes device engineering, in which multiple strands must conditionally adopt different structures depending on the subsets of strand species that are present.Intellectual MeritThe proposed research program seeks to develop analysis and design tools that will dramatically increase the level of rigor, accuracy, and automation with which nucleic acid devices are engineered. The work encompasses physical modeling, algorithm development, mechanism design, and experimental validation, with the unifying goal of enabling the manipulation of subtle features in the multiple energy landscapes that underlie the design of devices with many conditionally stable states. The development of a practical catalytic fuel delivery method and subsequent construction of a robust autonomous walker that can take hundreds of unassisted steps would represent a breakthrough in the field. Likewise, HCR provides a new functional paradigm for nucleic acid nanotechnology, creating many attractive avenues for investigation.Broader ImpactThe ability to engineer autonomous devices at the nanometer length scale may someday have importantmedical applications including the targeted delivery of toxic drugs. In the nearer term, HCR has the potential to facilitate the construction of versatile and inexpensive biosensors. Undergraduates have the opportunity to participate fully in this interdisciplinary research through the Caltech Summer Undergraduate Research Fellowship program. Researchers at other universities can freely download source code for the analysis and design software developed in the Pierce Lab. At Pasadena public schools, 62% of students participate in free or reduced-price meal programs and more than 80% of students are underrepresented minorities. For many students, the Jr. Teacher program will provide a rare opportunity to consider the attractions of pursuing a career in science or engineering.