Protein-peptide interactions
We are developing improved techniques for modeling of protein-peptide interactions in the context of protein design and high-throughput scoring and identification. We are also working on engineering and experimentally characterizing novel peptide-binding proteins with desired binding specificities.Proteins work in complexes, so their interaction partners are critical for understanding their biological function. Furthermore, many therapeutic strategies are aimed at disrupting or enhancing native protein-protein interactions. Predicting whether and how two proteins form a complex is thus a task of central importance. Beginning with the example of protein-peptide interactions, which are estimated to account for as much as 40% of all protein interactions in the cell, we are developing modeling methods, applicable in the context of design and rapid scoring. A robust solution to this problem will make possible the discovery of many biologically functional associations, and it will also enable the design of new peptide-based reagents.
Allosteric regulation
We are working on methods for the analysis and design of allosteric regulation by accurately accounting for the thermodynamic states involved. We hope to apply this methodology to both understand allosteric mechanisms in natural biological systems as well as demonstrate the practical design of allosteric regulation.Protein allostery, or the coupling of distant sites in a protein structure, is a fundamental element of many biological pathways. It is difficult to model accurately as it requires a detailed understanding of the structure/energy landscape. However, quantitative models of allostery are a necessity if we hope to understand biological signaling quantitatively and develop robust methods for the design of perturbative reagents. Further, the ability to design allostery would advance the newly emerging field of Protein Synthetic Biology. This branch of bioengineering aims to use protein building blocks to assemble reusable molecular parts and devices.
Protein design
Cells use proteins for a remarkable variety of tasks - from sensing and logic, to movement, to catalysis. Luckily, proteins are "programmable", in that their impressive array of functionality is, by and large, encoded using just twenty amino-acid building blocks. By learning the programming language of protein structure and function we can thus harness their rich functional diversity in making novel reagents. This is the task of protein design.The problem of computational protein design, that is the creation of novel protein sequences with desired structural and functional properties, has historically served the purpose of testing our understanding of the fundamental principles of protein structure and function. However, increasingly this problem is being looked at for its practical uses – the creation of novel functional protein-based reagents and therapeutics. Both of these facets are of interest to the lab and work on improved computational and experimental approach to the general problem of protein design is ongoing.