Institute for Protein Design

Research Areas

Research Overview

Forcefield development:   Protein 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.

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.

Parallel synthesis and screening:  Once 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.

Protein structure determination:  A 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.

 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.

The IPD is applying design methodology to a wide range of current challenges.  The main areas are described below. 

Design of new protein scaffolds:  In 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.

Design of protein binding:    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.

Design of small molecule binding:  The 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.

Design of enzymes:  The IPD is developing general methods for creating catalysts for chemical reactions not catalyzed by naturally occurring enzymes.

Design of self assembling nanomaterials:  Self 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.