John Santalucia

John Santalucia

Research interest(s)/area of expertise

Nucleic acid biophysical chemistry, structure and function, NMR structure determination, Ribosome structure and function, DNA and RNA Folding thermodynamics, structural bioinformatics of nucleic acids, 3D structure prediction of RNA, DNA based nanotechnology.

Research

There are three major research projects in our laboratory: 1) 3D structure prediction and analysis of RNA and DNA, 2) NMR structure determination of RNA with bound drugs and proteins, and 3) Nucleic acid-based nanotechnology.

Structural Bioinformatics of Nucleic Acids. The number of nucleic acid sequences in GenBank is increasing much faster than the 3D structures in the PDB. To address this problem, we are developing a suite of computational tools for nucleic acid sequence alignment, secondary structure prediction, de novo 3D structure prediction, 3D homology modeling (see figure), and structural analysis. Despite similarities to the protein folding problem, we have found that nucleic acids have unique characteristics that require new ideas. We are developing a new classical molecular simulation forcefield for nucleic acids and new conformational search methods. Important targets for structure prediction are the ribosomes from bacterial and eukaryotic pathogens. We are interested in developing methods that can automatically model both the RNA and protein components of ribosomes given the whole organism genome sequence. In addition, we are working to develop modeling methods for interactions of RNA with small molecules, which will enable virtual screening of new classes of drugs.

RNA Structure and Function. Our group uses NMR spectroscopy to solve atomic-resolution structures of biologically important RNAs. Comparison of the NMR structures of the wild-type and mutant sequences (collaboration with Dr. Philip Cunningham) allows for the determination of the key structural elements required for ribosome function. We are also studying the structure of RNA complexes with bound peptide ligands derived from library screening (collaboration with Dr. Christine Chow). The structures will be used to deduce the rules for RNA recognition and for rational design of peptidomimetics and refined drugs with improved pharmacokinetic properties.

Nucleic Acid Nanotechnology. An important goal of nanotechnology is to generate complex self-assembling molecular systems with predictable shape, dynamics, and catalytic properties. Both DNA and RNA have unique properties that make them well suited to nanotechnology applications. However, there has been a lack of understanding of 3D structure, molecular dynamics, hybridization kinetics and thermodynamics of nucleic acid self-assembly. Toward this problem, we are using our knowledge of nucleic acid 3D structure prediction, principles of hybridization and folding thermodynamics, and bioinformatics. The goal is to allow for the fully automated design of DNA and RNA nanostructures. Experimentally, we use a wide variety of techniques to characterize the structures including X-ray crystallography, electron microscopy, FRET, NMR, and gel electrophoresis. Our long-term goals are to improve the fundamental understanding of nucleic acid nano-structures, and also to make practical materials and devices.

Education

• B.S. Clarkson University, 1987
• Ph.D. University of Rochester, 1991
• NIH Postdoctoral Fellow, University of California, Berkeley, 1991-1994

Selected publications

• SantaLucia, J., Jr., Sozhamannan, S., Gans, J.D., Koehler, J.W., Soong, R., Lin, N.J., Xie, G., Olson, V. Roth, K., Beck, L.S. “Recommendations for Developing Molecular Assays for Microbial Pathogen Detection Using Modern In Silico Approaches,” J. AOAC Int., 103, 882-899 (2020).
• Hoshika, S., Leal, N.A., Kim, M.-J., Karalkar, N.B., Kim, M.-S., Bates, A.M., Watkins, N.E., Jr., SantaLucia, H.A., Meyer, A.J., DasGupta, S., Piccirilli, J.A., Ellington, A.D., SantaLucia, J., Jr., Georgiadis, M.M., Benner, S.A. “Hachimoji DNA and RNA: A Genetic System with Eight Building Blocks,” Science, 363, 884-887 (2019).
• SantaLucia, J., Jr., “How Much Free Energy is Absorbed Upon Breaking DNA Base Pairs?”, Physics of Life Reviews, 25, 29-33 (2018).
• Miao, Z. et al. “RNA-Puzzles Round III: 3D RNA structure prediction of five riboswitches and one ribozyme,” RNA, 23, 655-672 (2017).
• Jiang, J., Aduri, R., Chow, C.S., and SantaLucia, J., Jr. “Structure Modulation of helix 69 from Escherichia coli 23S ribosomal RNA by pseudouridylations,”, Nucleic Acids Res., doi:10.1093/nar/gkt1329, 42, 3971-81 (2014).

Citation index

•  Number of citations according to Web of Science as of April 1, 2023
• Total citations = 9166, H-index=31