David Baker, PhD

NGEC Principal Investigator

Professor, Biochemistry, University of Washington
Investigator, Howard Hughes Medical Institute

Department of Biochemistry
University of Washington School of Medicine
J Wing, Health Sciences Building, Box 357350
Seattle, WA 98195
Tel: 206-543-1295
Fax: 206-685-1792

E-mail Dr. Baker

Dr. Baker is a professor in the Department of Biochemistry at the University of Washington. He was recently appointed as a member of the National Academy of Sciences, and is internationally recognized for his role in computational prediction of protein folding, and the use of computational methods in protein design. His laboratory has ongoing research in myriad aspects of macromolecular structure prediction and design.

Dr. Baker is the principal investigator for the NGEC in the area of computational design of novel homing endonucleases.
 

Awards and Honors

• Foresight Institute Feynman Prize: 2004
• AAAS Newcomb Cleveland Prize: 2004
• International Society for Computational Biology Overton Prize: 2002
• Protein Society Young Investigator Award: 2000
• Beckman Young Investigator Award: 1995
• Packard Fellowship in Science and Engineering: 1994
• National Science Foundation Young Investigator Award: 1994
• Boyer Foundation Fellowship: 1993

Areas of Expertise

• Prediction of protein folding from sequence information
• Energetic analysis and optimization of protein-protein interfaces
• Computational redesign of protein interfaces for altered specificity
• Energetic modeling of protein-DNA interfaces

Research Interests

• Modeling water-mediated contacts in protein-DNA interfaces
• Improving structure predictions, especially at higher resolution
• Designing protein interactions with small molecules

Overview of the Baker Lab

The goal of current research in the Baker Laboratory is to develop an improved model of intra- and intermolecular interactions and to apply this improved model to the prediction and design of macromolecular structures and interactions. Prediction and design applications can be of great biological interest in their own right, and also provide very stringent and objective tests which drive the improvement of the model and increases in fundamental understanding.

The protein and design calculations are carried out using a computer program called RosettaDesign. RosettaDesign is a lab-developed, continually-refined computer program used for protein folding prediction and protein-protein and protein-DNA interface design.
At the core of RosettaDesign are the physical model of macromolecular interactions and algorithms for finding the lowest energy structure for an amino acid sequence (protein structure prediction) or a protein-protein complex, and for finding the lowest energy amino acid sequence for a protein or protein-protein complex (protein design). Both the physical model and the search algorithms are continually being improved based on feedback from the prediction and design tests.

There are considerable advantages in developing one computer program to treat these quite diverse problems: first, the different applications provide very complementary tests of the underlying physical model (the fundamental physical chemistry is, of course, the same in all cases), and second, many problems of current interest, such as flexible backbone protein design and protein-protein docking with backbone flexibility, involve a combination of the different optimization methods.

The Baker Lab has achieved significant advances in many areas, including the creation and ongoing development of RosettaDesign; the engineering of a homing endonuclease chimera (Chevalier et al, 2002); the design of a novel globular protein fold (Kuhlman et al, 2003); the thermostabilization of an enzyme (Korkegian et al, 2005) and the re-design of homing endonuclease DNA binding and cleavage specificity (Ashworth et al, 2006).
 

NGEC Research

For its role in the NGEC, the Baker Lab seeks to computationally design homing endonucleases that specifically cleave a desired target site. Dr. Baker and his team will use their computational design methodology — based on an explicit physical model of protein-DNA interfaces — to design novel homing endonuclease variants predicted to cleave specifically within sites in XSCID and other therapeutically important genes. Biochemical and biophysical data about first-generation designs will be used to refine and improve the lab’s computational design methodology.

Computational prediction and design of protein-DNA interfaces using RosettaDesign has made significant recent advances, culminating in the achievement of a designed specificity switch of the I-MsoI LHE by the Baker Lab. For the NGEC, the Baker Lab will further develop its RosettaDesign methods, and work to apply the new methods to the generation of LHEs for hematopoietic stem cell engineering.

The Baker Lab's NGEC work will be accomplished through three specific aims:

1. Apply computational design to generate new LHEs able to recognize and cleave at high-quality, engineerable match sites identified by PSSM analysis of target loci performed by the Monnat laboratory.
2. Refine RosettaDesign algorithms for prediction of DNA/protein interfaces by explicit incorporation of waters and rigid body framework movements.
3. Refine RosettaDesign algorithms for prediction of DNA/protein interfaces by explicit incorporation of structural information of novel LHE variants generated by the Stoddard lab.

Key personnel carrying out this research include Fabio Parmeggiani (postdoctoral fellow), Summer Thyme (graduate student) and Sandrine Boissel (graduate student).

Publications