Filtering by
- All Subjects: Proteins
- Creators: School of Molecular Sciences
- Creators: Wachter, Rebekka
- Member of: Theses and Dissertations
- Resource Type: Text
- Status: Published
A novel flexible docking approach called BP-Dock (Backbone Perturbation docking) was developed to overcome this challenge. BP-Dock integrates both backbone and side chain conformational changes of a protein through a multi-scale approach. In BP-Dock, the residues along a protein chain are perturbed mimicking the binding induced event, with a small Brownian kick, one at a time. The fluctuation response profile of the chain upon these perturbations is computed by Perturbation Response Scanning (PRS) to generate multiple receptor conformations for ensemble docking. To evaluate the performance of BP-Dock, this approach was applied to a large and diverse dataset of unbound structures as receptors. Furthermore, the protein-peptide docking of PICK1-PDZ proteins was investigated. This study elucidates the determinants of PICK1-PDZ binding that plays crucial roles in numerous neurodegenerative disorders. BP-Dock approach was also extended to the challenging problem of protein-glycan docking and applied to analyze the energetics of glycan recognition in Cyanovirin-N (CVN), a cyanobacterial lectin that inhibits HIV by binding to its highly glycosylated envelope protein gp120. This study provide the energetic contribution of the individual residues lining the binding pocket of CVN and explore the effect of structural flexibility in the hinge region of CVN on glycan binding, which are also verified experimentally. Overall, these successful applications of BP-Dock highlight the importance of modeling backbone flexibility in docking that can have important implications in defining the binding properties of protein-ligand interactions.
Finally, an induced fit docking approach called Adaptive BP-Dock is presented that allows both protein and ligand conformational sampling during the docking. Adaptive BP-Dock can provide a faster and efficient docking approach for the virtual screening of novel targets for rational drug design and aid our understanding of protein-ligand interactions.
Non-canonical amino acids (NCAAs) can be used in protein chemistry to determine their structures. A common method for imaging proteins is cryo-electron microscopy (cryo-EM) which is ideal for imaging proteins that cannot be obtained in large quantities. Proteins with indistinguishable features are difficult to image using this method due to the large size requirements, therefore antibodies designed specifically for binding these proteins have been utilized to better identify the proteins. By using an existing antibody that binds to stilbene, NCAAs containing this molecule can be used as a linker between proteins and an antibody. Stilbene containing amino acids can be integrated into proteins to make this process more access able. In this paper, synthesis methods for various NCAAs containing stilbene were proposed. The resulting successfully synthesized NCAAs were E)-N6-(5-oxo-5-((4-styrylphenyl) amino) pentanoyl) lysine, (R,E)-2-amino-3-(5-oxo-5-((4-styrylphenyl)amino)pentanamido)propanoic acid, (E)-2-amino-5-(5-oxo-5-((4-styrylphenyl) amino) pentanamido) pentanoic acid. A synthesis for three more shorter amino acids, (R,E)-2-amino-3-(3-oxo-3-((4-styrylphenyl) amino) propanamido) propanoic acid, (E)-2-amino-5-(3-oxo-3-((4-styrylphenyl) amino) propanamido) pentanoic acid, and (E)-N6-(3-oxo-3-((4-styrylphenyl) amino) propanoyl) lysine, is also proposed.