Our research answers biological questions through a structural perspective and applies the knowledge gained towards drug discovery. Till 2017, we primarily employed computational approaches for structure prediction, drug design, and analysis of biomolecular dynamics. We have since incorporated single particle cryo-electron microscopy (cryo-EM) as our primary research tool in close collaboration with the Agrawal group. The present research areas are:
Macromolecular structure-function and drug design: In collaboration with the Agrawal group, we are using cryo-EM to resolve structures of bacterial and human mitochondrial ribosomal complexes. Cryo-EM studies of the human mitochondrial ribosome in complex with protein translation factors are being performed in collaboration with the Agrawal group (e.g. Koripella et al., Nat. Comm. 2021; Koripella et al., Nat. Comm., 2020). The bacterial ribosome studies are focused on pathogenic ribosome hibernation mechanisms, protein factor roles in ribosome function, and antibiotic design. This work is being pursued in collaboration with the Agrawal, Ojha, Ghosh, Derbyshire, Gray, and Wade groups at the Wadsworth Center (e.g. Li et al. Microbiol. 2021). We also aim to utilize our structural findings towards biomedical gains through computational inhibitor discovery and design. Prior achievements in translational medicine include discovery of inhibitors targeted towards Flaviviruses such as Dengue and West Nile Virus in collaboration with the Li and Kramer groups (e.g. Li et al., Cell Res., 2017; Brecher et al. PLoS One, 2015; Chen et al. Antiviral Res. 2013).
Biochemical reaction mechanisms: Our strategy called Restrained Bonds And Topology Switching (RGATS) (Manjari and Banavali, J. Chem. Inf. Model., 2018) can obtain atomic-detail trajectories for biochemical reactions using standard biomacromolecular Molecular Mechanics programs. It can rapidly explore different postulated mechanisms in 3D atomic detail, and can predict reactant, intermediate, and product states when the structure is known or can be modeled in any one of these states. The strategy has been successfully applied to model different reactions such as: (a) Proton transfer in an ammonia transporter, (b) Nucleic acid strand extension in DNA polymerases, (c) Hedgehog protein autoprocessing (Banavali, J. Comput. Chem, 2020). This work includes collaborations with Dr. Chunyu Wang at RPI, Dr. Brian Callahan at Binghamton University, and Dr. Marlene Belfort at UAlbany.
Biomolecular dynamics: We have a continuing interest in understanding macromolecular function in the context of underlying free energy landscapes. One example of many is our delineation of the 3D strand slippage mechanism by which a single base insertion or deletion (indel) mutation can occur in DNA strand extension and identifying how specific non-canonical interactions providing a direct mechanism for sequence dependence of indel mutations (Banavali, J. Am. Chem. Soc., 2013).
Our long-range goals are to broaden our present expertise in atomic-scale understanding of chemical change and molecular recognition to a larger length scale to explain how macromolecular components interact and coordinate their activity to form functional nanoscale cellular machinery.
Affiliation: Wadsworth Center, New York State Department of Health
- Macromolecular structure-function
- Since-particle cryo-electron microscopy
- Structure-based drug discovery and design
- Biomolecular reaction mechanisms and dynamics
- Drug Discovery & Therapeutics
- Structural Biology