Computational Exploration of a Protein Receptor Binding Space with Student Proposed Peptide Ligands

<p> Computational molecular docking is a fast and effective <em> in silico </em> method for the analysis of binding between a protein receptor model and a ligand. The visualization and manipulation of protein to ligand binding in three-dimensional space represents a powerful tool in the biochemistry curriculum to enhance student learning. The DockoMatic tutorial described herein provides a framework by which instructors can guide students through a drug screening exercise. Using receptor models derived from readily available protein crystal structures, docking programs have the ability to predict ligand binding properties, such as preferential binding orientations and binding af&filig;nities. The use of computational studies can signi&filig;cantly enhance complimentary wet chemical experimentation by providing insight into the important molecular interactions within the system of interest, as well as guide the design of new candidate ligands <strong> </strong> based on observed binding motifs and energetics. In this laboratory tutorial, the graphical user interface, DockoMatic, facilitates docking job submissions to the docking engine, AutoDock 4.2. The purpose of this exercise is to successfully dock a 17-amino acid peptide, &alpha;-conotoxin TxIA, to the acetylcholine binding protein from <em> Aplysia californica </em> -AChBP to determine the most stable binding con&filig;guration. Each student will then propose two speci&filig;c amino acid substitutions of &alpha;-conotoxin TxIA to enhance peptide binding af&filig;nity, create the mutant in DockoMatic, and perform docking calculations to compare their results with the class. Students will also compare intermolecular forces, binding energy, and geometric orientation of their prepared analog to their initial &alpha;-conotoxin TxIA docking results.</p>