Protein binding to small molecules is fundamental to many biological processes, yet it remains challenging to predictively design this functionality de novo. Current state-of-the-art computational design methods typically rely on existing small molecule binding sites or protein scaffolds with existing shape complementarity for a target ligand. Here we introduce new methods that utilize pools of discrete contacts observed in the Protein Data Bank between protein residues and defined small molecule ligand substructures (ligand fragments). We use the Rosetta Molecular Modeling Suite to recombine protein residues in these contact pools to generate hundreds of thousands of energetically favorable binding sites for a target ligand. These composite binding sites are built into existing scaffold proteins matching the intended binding site geometry with high accuracy. In addition, we apply pools of rotamers interacting with the target ligand to augment Rosetta’s conventional design machinery and improve key metrics known to be predictive of design success. We demonstrate that our method reliably builds diverse binding sites into different scaffold proteins for a variety of target molecules. Our generalizable de novo ligand binding site design method will lay the foundation for versatile design of protein to interface previously unattainable molecules for applications in medical diagnostics and synthetic biology.

At the outset of this research, there was significant doubt as to whether incumbent solar photovoltaic semiconductors, particularly silicon, would be sufficiently available, efficient, and affordable to meet the growing demand for solar cells. Chapter 1 is an introduction that frames some of the challenges with developing new semiconductor materials. In short, I encourage any researcher pursuing new materials to take a more holistic view of many material properties which contribute to photovoltaic performance rather than over-focusing on a single property to the exclusion of others.

This dissertation explores two distinct routes, one experimental and one computational, to achieving future photovoltaics with the potential for either higher efficiency or lower cost. Chapter 2 presents one of the first colloidal nanocrystal syntheses of a novel, earth-abundant semiconductor, FeS2, better known as "fool's gold" or "iron pyrite". This particular synthesis is controlled by an aliphatic sulfonate ligand, a new ligand in the field of nanocrystal synthesis. In contrast, Chapter 3 takes a theoretical approach by using combinatorial density functional theory calculations to identify which dopants would be most likely to generate favorable electronic energy levels in zinc sulfide. The goal of the computation is to identify the dopant-matrix most likely to form the absorber layer for an intermediate band solar cell.

Lastly, Chapter 4 is an outlook that compiles a variety of categorical approaches, as well as specific techniques, for improving device efficiency and/or lowering costs. Since this field is sure to experience both incremental and step-change progress, keeping new approaches in mind is essential to planning future research activities.