Applications and Improvements in the Molecular Modeling of Protein and Ligand Interactions

Understanding protein and ligand interactions is fundamental to treat disease and avoid toxicity in biological organisms. Molecular modeling is a helpful but imperfect tool used in computer-aided toxicology and drug discovery. In this work, molecular docking and structural informatics have been integrated with other modeling methods and physical experiments to better understand and improve predictions for protein and ligand interactions. Results presented as part of this research include:

1.) an application of single-protein docking for an intermediate state structure, specifically, modeling an intermediate state structure of alpha-1-antitrypsin and using the resulting model to virtually screen for chemical inhibitors that can treat alpha-1-antitrypsin deficiency,

2.) an application of multi-protein docking and metabolism prediction, specifically, modeling the cytochrome P450 metabolism and estrogen receptor activity of an environmental pollutant (PCB-30), and

3.) providing evidence to support the inclusion of anion-pi interactions in molecular modeling by demonstrating the biological roles of anion-pi interactions in stabilizing protein and protein-ligand structures.

This work has direct applications for mitigating disease and toxicity, but it also demonstrates useful ways of integrating computational and experimental data to improve upon modeling protein and ligand interactions.