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 Biochemistry. In the graduate program, Dr. Lyubchenko teaches in PHSC-845: Quantitative Pharmaceutical Sciences, PHSC-921/BIOC-921: Biophysical Chemistry. He also coordinates and teaches 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. We also have a keen interest in new and innovative instrumentation, working on development of novel nanoimaging and nanoprobing approaches.
The projects are funded by one NSF and four NH grants.
In area 1, the structural genomic area we discovered highly dynamic inherent property of nucleosomes based on the direct imaging of nucleosomes with time lapse AFM and identified a critical role of electrostatics in their spontaneous dynamics. The current project deals with characterization of centromere chromatin. Centromeres are specialized segments of chromosomes that aid in faithful chromosomal segregation after DNA replication. If the centromere becomes damaged or removed, chromosomes segregate randomly triggering cancer development. We proposed a model according to which changes in the nucleosome wrapping lead to considerable changes in the CENP-A nucleosome array. The application of the cutting-edge high-speed AFM approach led to the discovery that that CENP-A stabilizes nucleosome core particles against complete dissociation even when they are not fully wrapped with DNA. The stability of centromeric nucleosomes is a critical property of centromeres. This novel property of CENP-A permits rapid nucleosome re-assembly following mitosis, transcription or replication induced eviction. This behavior of CENP-A might then contribute to its longevity on the chromatin fiber, thus contributing to the cell cycle independent “memory” of centromeric chromatin over several cell cycles.
The availability of new AFM methodology was critical for his studies of the interaction of site-specific DNA binding proteins as well as regulation of DNA replication and recovery from stalling of the replication machinery. These studies led to the discovery a novel property of SSB protein that in the interaction with RecG protein it works as a remodeling protein. This remodeling changes the mode of RecG-replication fork interaction allowing the protein to slide along the parental arm of the replication fork. Single-molecule high-speed AFM approach made it possible to directly visualize this effect.
Area 2: molecular mechanisms Alzheimer’s, Parkinson’s and similar protein misfolding diseases
We developed novel approaches for probing aggregation-prone transient states of amyloid proteins with AFM force spectroscopy. 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 is further supported by theoretical analyses in which he utilizes the most powerful computational resources in the nation. The combination of nanoimaging techniques with high-power computational modeling led to the discovery a novel pathway for spontaneous assembly of amyloid peptides and proteins that occurs at the physiological concentration range. These novel findings not only eliminate a major problem with understanding the spontaneous appearance of plaques in the brain of Alzheimer’s patients at physiological range of protein concentrations, but reveals a number of important properties of the on-surface aggregation process. A novel model of the amyloid aggregates assembly in which change in membrane properties leading to an increase in affinity of amyloid proteins to the membrane surface triggers the disease-related aggregation process. The proposed model is a significant departure from the current model in which amyloid aggregation is linked with elevated synthesis of amyloid proteins. This is a paradigm shift in the development of efficient treatments and diagnostics for protein aggregation neurodegenerative diseases.
Area 3: protein-DNA interactions and development of approaches for HIV restriction
In this area, we are working on approaches utilizing factors that provide innate immunity against HIV-1. We has developed advanced experimental AFM approaches that allowed him to characterize, at the nanoscale, complexes formed by A3G HIV restriction factor and ssDNA. These techniques enabled us to directly image the sliding of A3G along the substrate. Furthermore, he discovered and characterized the process where A3G self-assembles into oligomers. Together, his studies determined a number of novel features of A3G-ssDNA complexes, thus paving the road for new therapeutic interventions. These approaches are discussed at regular annual NIH/NIGMS meetings “Structural Biology Related to HIV/AIDS” at which Lyubchenko is invited to speak.
Dr. Lyubchenko is getting invitations for editing books by the top publishers. The CRC Press has published an edited textbook “An Introduction to Single Molecule Biophysics” that has two chapters prepared by Lyubchenko’s lab. He is currently working on the Nanoimaging volume for book series Methods in Molecular Biology, publishing by Springer Nature. Over 1500 books have been published to date in this book series widely used by biomedical scientists.
- Sun, Z., Tan, H. Y., Bianco, P. R., and Lyubchenko, Y. L. (2015) Remodeling of RecG Helicase at the DNA Replication Fork by SSB Protein, Sci Rep 5, 9625.
- Lyubchenko, Y. L., and Shlyakhtenko, L. S. (2016) Imaging of DNA and Protein-DNA Complexes with Atomic Force Microscopy, Crit Rev Eukaryot Gene Expr 26, 63-96.
- Maity, S., Viazovkina, E., Gall, A., and Lyubchenko, Y. (2016) A Metal-free Click Chemistry Approach for the Assembly and Probing of Biomolecules, Journal of Nature and Science 2, e187.
- Proctor, E. A., Fee, L., Tao, Y., Redler, R. L., Fay, J. M., Zhang, Y., Lv, Z., Mercer, I. P., Deshmukh, M., Lyubchenko, Y. L., and Dokholyan, N. V. (2016) Nonnative SOD1 trimer is toxic to motor neurons in a model of amyotrophic lateral sclerosis, Proc Natl Acad Sci U S A 113, 614-619.
- Shlyakhtenko, L. S., Dutta, S., Li, M., Harris, R. S., and Lyubchenko, Y. L. (2016) Single-Molecule Force Spectroscopy Studies of APOBEC3A-Single-Stranded DNA Complexes, Biochemistry 55, 3102-3106.
- Zhang, Y., Hashemi, M., Lv, Z., and Lyubchenko, Y. L. (2016) Self-assembly of the full-length amyloid Abeta42 protein in dimers, Nanoscale 8, 18928-18937.
- Banerjee, S., Hashemi, M., Lv, Z., Maity, S., Rochet, J. C., and Lyubchenko, Y. L. (2017) A novel pathway for amyloids self-assembly in aggregates at nanomolar concentration mediated by the interaction with surfaces, Sci Rep 7, 45592.
- Banerjee, S., Sun, Z., Hayden, E. Y., Teplow, D. B., and Lyubchenko, Y. L. (2017) Nanoscale Dynamics of Amyloid beta-42 Oligomers As Revealed by High-Speed Atomic Force Microscopy, ACS Nano 11, 12202-12209.
- Gorle, S., Pan, Y., Sun, Z., Shlyakhtenko, L. S., Harris, R. S., Lyubchenko, Y. L., and Vukovic, L. (2017) Computational Model and Dynamics of Monomeric Full-Length APOBEC3G, ACS Cent Sci 3, 1180-1188.
- Maity, S., Viazovkina, E., Gall, A., and Lyubchenko, Y. L. (2017) Single-molecule probing of amyloid nano-ensembles using the polymer nanoarray approach, Phys Chem Chem Phys 19, 16387-16394.
A complete list of publications, excluding chapters and articles not accessed by PubMed, can be found here.