Comparative Analysis of D3 Dopamine Receptor Binding Profiles Using ChimeraX​

• Serena Foko, Biological Sciences, University of Delaware

• David Raden, Department of Biological Sciences, University of Delaware

The D3R protein receptor is a key brain protein that regulates reward pathways and influences addiction, habit formation, and relapse. The receptor’s binding pocket acts like a precise lock designed for specific molecular keys (ligands). Proteins are not static; instead, they possess intrinsic energy, dynamically shifting between conformations. Binding to a specific drug drives the receptor into an “on” (active) or “off” (inactive) state. Understanding how different drug molecules alter pocket interactions to drive these shape changes is critical for advancing addiction research.

Molecular visualization provides a powerful tool to analyze these dynamic structures. In this study, I used UCSF ChimeraX to perform a comparative structural analysis between an inactive state bound to an antagonist and an active state bound to an agonist alongside a Gᵢ helper protein. By mastering ChimeraX command-line tools and display settings, I developed foundational skills in computational protein analysis.

I examined both structures in full-atom detail to analyze structural changes across the protein. At the macro level, the agonist causes the receptor to open on the cytosolic side so the Gᵢ protein can attach and trigger signaling, while the antagonist keeps the receptor closed. At the micro level, I highlighted amino acid anchors to show how both drugs attach inside the pocket while holding the receptor in distinct shapes. Ultimately, combining computational drug screening with human structural analysis enables precise evaluation of binding pockets, accelerating the search for targeted addiction therapies.