Proteins are biological macromolecules that serve a variety of roles in the body, such as providing structural support, transporting molecules around the body, supporting immune function, and facilitating muscle contraction. For these proteins to perform their role, they must fold properly. Some proteins fold spontaneously while others require the help of specialized proteins known as molecular chaperones. To fold client proteins, the Hsp90 chaperone undergoes large conformational changes driven by nucleotides. Molecular dynamics (MD) simulations are a useful tool to study protein dynamics. However, due to the large system size of Hsp90, all atom Explicit Solvent simulations on relevant time scales are very expensive. In this study, we propose using a method known as Target MD Simulation with Implicit Solvent to understand the mechanism of client remodeling by the bacterial Hsp90.
The bacterial Hsp90 comprises about 55% in-sequence identity to the human Hsp90. Like other Hsp90s, it is composed of the nucleotide binding domain (NTD) that binds ATP, the middle domain (MD) that binds client proteins, and the C-terminal domain (CTD) for dimerization. To promote remodeling of the client, the bacterial Hsp90 collaborate with Hsp70 and its co-chaperone to reactivate inactivated model clients.
Successful docking of the client (Δ131Δ) staphylococcal nuclease into the APO structure was the first step to the complex process of visualizing the transitions between various chaperone states and its interactions with the substrate.
By using the optimized structure, we will run TMD simulations to model the open to closed to semi-closed to open models of the Hsp90 protein chaperone. This will provide detailed insight into the molecular interactions between the client and chaperone through the nucleotide transitions.
Author(s): Meghana Sugoor, Biology Major
Advisor(s): Andrea Kravats – Department of Chemistry and Biochemistry
Ikponwmosa Obaseki, Hannah Popoola – Department of Chemistry and Biochemistry
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