Basic Areas of Research

Proteins mediate the fundamental processes of life, and the beautiful and varied ways in which they do this has been the focus of much of the biomedical research of the past 50 years. Protein based materials have remarkable potential for solving a vast array of technical challenges: natural proteins mediate the use of solar energy to manufacture complex molecules, ultrasensitive detection of small molecules (olfactory receptors), ultrasensitive detection of light (rhodopsin), conversion of pH gradients to chemical bond formation (ATP synthase), transformation of chemical energy into work (actin), just to name a few. These complex functions are encoded extremely economically in amino acid sequences, and the assembly process is largely spontaneous. With all the advances in technology of the past 100 years, there are no human-made machines that can compete with the precision of function at the nanoscale and the ease of manufacturing. The properties of natural proteins are even more amazing considering that they are essentially historical accidents. There was no well thought out plan to develop a machine to use proton flow to convert ADP to ATP; instead, there was selective pressure operating on a pool of random variants of primordial proteins, and hundreds of millions of years to get it right.
Evolution has done an incredible job making these proteins with exquisite functions, but nature can only do so much. Modern day challenges demand new proteins with new functions on a much faster timescale than evolution is capable of. The goal of the IPD is to develop and apply methods for designing this new world of synthetic proteins to address these challenges. Below are some of the areas in which our research is focused.

Design of New Protein Scaffolds

Design of Ideal Folded ProteinsIn the past, almost all protein design and engineering efforts have modified naturally occurring protein backbones.  However, for most challenges there is unlikely to already exist in nature a backbone with an optimal geometry.  The IPD is developing general methods for designing a wide range of exceptionally stable protein structures with tunable geometries for specific applications. See Proteins Made to Order, and vaccine design for HIV and RSV.

Design of Protein Binding

Designed pH-dependent Fc binder (blue) exploits protonation of Histidine-433 (orange) in the Fc portion Immunoglobulin G (IgG, light cyan surface)

Like most biological entities, viruses and tumor cells have specific proteins on their surfaces.  Hence, designed proteins which 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 binding, and applying these methods to design binders to targets of biomedical interest.  These efforts are providing fundamental insights into the protein-protein interactions which underlie most cellular processes.  See Flu BinderFc Binder, and Lysozyme Inhibitor.

Design of Small Molecule Binding

DIGbinderthumbnailThe IPD is developing general methods for design proteins to 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.  See Digoxigenin BinderPreparing Scaffold Libraries, and Metal Binder.

Design of Enzymes

Sridhar_triadThe IPD is developing general methods for creating catalysts for chemical reactions not catalyzed by naturally occurring enzymes. See Enzyme DesignKumaMax, and Serine Catalytic Triad Design.

Design of Self-Assembling Nanomaterials

TwoComponentthumbnailSelf assembling protein materials play critical roles in biology.  IPD researchers are developing general approaches for creating new self assembling nanostructures, and using these approaches to develop a next generation of vaccines and drug delivery vehicles. See Self-Assembling Nanomaterials and Two-Component Nanomaterials.

Forcefield Development

RosettaCMProtein design methodology seeks 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 the ~100,000 protein crystal structures to improve our description of protein energetics on the atomic scale.  See Comparative Modeling with RosettaCM.

Sampling Algorithm Development

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.  See Sampling Algorithm Development.

Parallel Synthesis and Screening

Flu BindersOnce low energy designed proteins have been identified on the computer, it is critical to test these experimentally.  Since neither the design forcefield nor the sampling methods are perfect, it is desirable 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.  See Optimizing Flu Binders.

Protein Structure Determination

Tools for Structure DeterminationA test of the accuracy of the forcefield and the thoroughness of the backbone sampling methodology that is of great importance in its own right is the protein structure determination problem.  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.  See Prediction of Symmetric AssembliesEnergy and Density RefinementStructure Determination from Low-Resolution Data, and Model Building for CryoEM.

Involving the General Public

The IPD seeks to involve the general public as much as possible in its research activities both for education and research purposes.  The distributed computing project Rosetta@Home and the online protein design game FoldIt have both attracted over 300,000 participants.  Learn how you can Participate.