Department of Pharmaceutical Sciences
College of Pharmacy
University of Nebraska Medical Center
986025 Nebraska Medical Center
Omaha, NE 68198-6025
In professional program, Dr. Lyubchenko teaches PHSC 691 Pharmaceutical Science Applications in Pharmacy and PHSC520: Pharmaceutical Biotechnology and Biochemistry. In the graduate program, Dr. Lyubchenko teaches in PHSC-845: Quantitative Pharmaceutical Sciences, PHSC-921/BIOC-921: Biophysical Chemistry, Biochemistry 850: Laboratory Techniques in Biochemistry and Molecular Biology. He also coordinates a PHSC 848 course: Bioimaging and Nanoimaging focused on applications of nanotechnology to pharmaceutical science and biomedicine.
Research in the Lyubchenko lab (Pharmaceutical Nanoimaging and Nanoengineering Laboratory, PNNL) focuses on understanding fundamental mechanisms underlying health and disease, which are key to developing new and more effective diagnostics and medications. This primarily basic research allows us not only identifies new drug targets for small molecule drugs, it also develops the tools and methods to discover novel approaches for diagnostic, treatment and disease prevention and to more rapidly determine their efficacy at the molecular level. The research is categorized into four broad areas, with interplay and overlap among them (1) Structural genomics in relation to cancer and other diseases, (2) Molecular mechanisms Alzheimer’s, Parkinson’s and other protein aggregation diseases, (3) Protein-DNA interactions for novel approaches for HIV restriction (4) Development of novel nanoimaging and nanoprobing approaches.
The projects are funded by one NSF and four NH grants.
In area 1, a highly dynamic inherent property of nucleosomes was discovered. This discovery was made by the use of time-lapse AFM in water and these studies identified a critical role of electrostatics in their spontaneous dynamics. The current project deals with the characterization of centromere chromatin. Centromeres are specialized segments of chromosomes that aid chromosomal segregation after DNA replication. If the centromere becomes damaged or removed, chromosomes segregate randomly triggering cancer development. A novel model according to which changes in the nucleosome wrapping lead to considerable changes in the CENP-A nucleosome array was proposed. This model not only explains the incongruences in AFM studies for CENP-A and H3-chromatin but set a foundation for understanding of chromatin dynamics. The current research revolves around testing this model and characterizing structural and dynamics properties of centromere and bulk chromatin.
The availability of new AFM methodology was critical for studies of interaction of site-specific DNA binding proteins as well as regulation of DNA replication with RecG protein.
Area 2: molecular mechanisms Alzheimer’s, Parkinson’s and similar protein misfolding diseases
In the protein misfolding area fundamental contributions to understanding molecular mechanisms of such neurodegenerative disorders as Parkinson’s, Alzheimer’s, and Huntington’s diseases have been made. Novel approaches for probing of transient misfolded states of proteins were developed and applied to various amyloid systems. The major discovery is that a misfolding amyloid dimer has an extremely long lifetime in comparison with the fast conformational dynamics of monomers. Such stabilization dramatically facilitates the aggregation kinetics and thus triggers the entire aggregation process. This conclusion is in line with recent findings on the critical role of dimers in the self-assembly of proteins and supported by theoretical analyses in which he utilizes national most powerful computational resources.
Area 3: protein-DNA interactions and development of approaches for HIV restriction
In this area, understanding of molecular mechanism of interaction with DNA APOBEC3 (A3) proteins that considered as innate immune system against HIV is the major focus. Nanoimaging experimental AFM approaches were developed and applied to characterize complexes formed by A3G HIV restriction factor and ssDNA. Using these techniques, sliding of A3G along the substrate was directly visualized. Together, these studies revealed a number of novel features of A3G-ssDNA complexes, thus paving the road for new therapeutic interventions.
Area 4: The technology development area
The nanotechnology development has always been an integral part of all of all research projects in the Lyubchenko lab. Note the sample preparation procedure developed for AFM imaging of DNA, RNA and protein-nucleic acid system that made it possible to direct time-lapse imaging of various nucleoprotein complexes. This technology will be applied in all current applications. Note that the Lyubchenko lab is equipped with the high-speed AFM instrument enabling direct visualization of the function of biological machines and assemblies at nanoscale in real time. He collaborates with Prof. T. Ando, the instrument inventor (Kanzawa University) as well laboratories of Prof. C. Bustamante (UC Berkeley) and Dr. A. Noy (LNL, Livermore) on further development of this cutting-edge technology.
- Krasnoslobodtsev, A. V., T. Deckert-Gaudig, Y. Zhang, V. Deckert and Y. L. Lyubchenko (2016). "Polymorphism of amyloid fibrils formed by a peptide from the yeast prion protein Sup35: AFM and Tip-Enhanced Raman Scattering studies." Ultramicroscopy 165: 26-33.
- Krasnoslobodtsev, A. V., M. P. Torres, S. Kaur, I. V. Vlassiouk, R. J. Lipert, M. Jain, S. K. Batra and Y. L. Lyubchenko (2015). "Nano-immunoassay with improved performance for detection of cancer biomarkers." Nanomedicine : nanotechnology, biology, and medicine 11(1): 167-173.
- Lv, Z., A. V. Krasnoslobodtsev, Y. Zhang, D. Ysselstein, J. C. Rochet, S. C. Blanchard and Y. L. Lyubchenko (2015). "Direct Detection of alpha-Synuclein Dimerization Dynamics: Single-Molecule Fluorescence Analysis." Biophys J 108(8): 2038-2047.
- Lyubchenko, Y. L. (2014). "Centromere chromatin: a loose grip on the nucleosome?" Nature structural & molecular biology 21(1): 8.
- Lyubchenko, Y. L. (2014). "Nanoscale Nucleosome Dynamics Assessed with Time-lapse AFM." Biophysical Reviews 6(2): 181-190.
- Lyubchenko, Y. L. and L. S. Shlyakhtenko (2016). "Imaging of DNA and Protein-DNA Complexes with Atomic Force Microscopy." Critical Reviews in Eukaryotic Gene Expression 26(1): 63-96.
- Proctor, E. A., L. Fee, Y. Tao, R. L. Redler, J. M. Fay, Y. Zhang, Z. Lv, I. P. Mercer, M. Deshmukh, Y. L. Lyubchenko and N. V. Dokholyan (2016). "Nonnative SOD1 trimer is toxic to motor neurons in a model of amyotrophic lateral sclerosis." Proc Natl Acad Sci U S A 113(3): 614-619.
- Seamon, K. J., Z. Sun, L. S. Shlyakhtenko, Y. L. Lyubchenko and J. T. Stivers (2015). "SAMHD1 is a single-stranded nucleic acid binding protein with no active site-associated nuclease activity." Nucleic Acids Res 43(13): 6486-6499.
- Shlyakhtenko, L. S., S. Dutta, J. Banga, M. Li, R. S. Harris and Y. L. Lyubchenko (2015). "APOBEC3G Interacts with ssDNA by Two Modes: AFM Studies." Sci Rep 5: 15648.
- Sun, Z., H. Y. Tan, P. R. Bianco and Y. L. Lyubchenko (2015). "Remodeling of RecG Helicase at the DNA Replication Fork by SSB Protein." Sci Rep 5: 9625.
A complete list of publications, excluding chapters and articles not accessed by PubMed, can be found here.