Basic Areas of Research
Proteins already solve a vast array of technical challenges: in nature, they mediate the use of solar energy to manufacture complex molecules, respond to small molecules and light, convert chemical gradients to chemical bonds and transform chemical energy into work — just to name a few.
Our researchers draw inspiration from nature’s proteins and work to design equally useful molecules from scratch.
In the past, almost all protein design efforts have modified naturally occurring protein backbones. However, for most challenges, there is unlikely to already exist a protein with an optimal 3D structure. The IPD is developing methods for designing a wide range of exceptionally stable protein structures with tunable geometries for specific applications.
Viruses and tumor cells have specific proteins on their surfaces. Hence, designed proteins that bind target proteins with high affinity and specificity could be broadly useful as both therapeutics and diagnostics. The IPD is developing methods for designing high-affinity protein binding and applying these methods to create binders to targets of medical interest. These efforts are providing fundamental insights into the protein-protein interactions which underlie most cellular processes.
Similarly, the IPD is developing methods for designing proteins that bind with high affinity to small molecules and applying these methods to design binders for drugs with narrow therapeutic windows, toxic compounds and other small molecules of interest. These efforts inform our understanding of small molecule recognition in biology.
Self-assembling protein materials play critical roles in biology. IPD researchers are developing new self-assembling nanostructures and using these approaches to develop the next generation of vaccines and drug delivery vehicles.
Enzymes catalyze chemical reactions that are essential for life. The IPD is developing general methods for creating catalysts for chemical reactions not catalyzed by naturally occurring enzymes.
Our protein design methods seek the lowest energy amino acid sequence given constraints specifying the problem of interest. The more accurate the force field used to calculate energies, the higher the activity and success rates of the designed proteins. IPD researchers use a combination of physical chemistry and analysis of over one hundred thousand protein crystal structures to improve our description of protein energetics on the atomic scale.
Given an accurate force field, the design problem becomes finding the lowest energy sequence for a given challenge. Since there are 20 amino acids possible at each position, this may require searching through the 20x20x20…=20Nres sequences for a new designed protein with Nres residues. Because the optimal structure to solve a given challenge is in general not known in advance, alternative backbone conformations must be searched as well—also a challenge since even with the conservative estimate of three states per residue there are ~3Nres conformations for an Nres protein. IPD researchers are developing algorithms for efficiently searching through these vast sequence and structure spaces to find very low energy solutions that solve the specified design challenge.
Once low-energy designed proteins have been identified on the computer, it is critical to test them experimentally. Since neither the design tools nor the sampling methods are perfect, we seek to experimentally manufacture and measure the activity of as many designs as possible. IPD researchers are developing methods for experimentally testing tens of thousands of different computational designs in parallel.
IPD researchers are developing powerful methods for solving protein structures using limited experimental data that are being used to solve naturally occurring protein structures in laboratories around the world.