M. Reza Ghadiri
Department of Chemistry, MB-9
Scripps Research Institute
10666 North Torrey Pines Road
La Jolla, CA 92037
1991 Searle Scholar
Organic, Bioorganic and Nanochemistry
- Molecular Design
- Chemical, Biological and Materials Science Applications
- De Novo Design of Artificial Proteins and Catalysts
- Protein Folding on the Nanosecond Time Scale
- Design of Self-Replicating Molecular Systems
- Novel Antibiotics and Cytotoxic Agents
The Ghadiri group is involved in a multidisciplinary research effort that uses disciplines ranging from synthetic organic and inorganic chemistry to materials science and recombinant DNA technology to develop novel methods for the rational design and construction of biomaterials-based membrane channels, artificial proteins, molecular receptors, and enzymes. Currently, research projects in our laboratory deal with various aspects of peptide architecture, design of artificial metalloproteins, protein folding and stability, molecular recognition, catalyst design, design of self-replicating molecular systems, and nanochemistry.
Peptide and Protein Architecture. Because of their key biological roles, proteins have been prime targets for design. The major obstacle in the biomimetic design of proteins from linear polypeptide sequences is the lack of comprehensive understanding of how one-dimensional sequence information directs formation of a discrete three-dimensional state of a protein. An alternative organizing molecular processes by which small structure peptides can be assembled into large and topologically predetermined protein tertiary structures. In our approach, the intrinsic binding energy of metal ion-ligand interactions is exploited to drive and control formation of protein secondary and tertiary structures. Recent examples of protein design in our laboratory include spontaneous self-assembly of a 15-residue peptide into a 45-residue parallel three-helix bundle metalloprotein, design of a 64-residue four-helix bundle ruthenium (II) metalloprotein, and construction of the first de novo designed heterobimetallic RuII.CuII three-helix bundle protein. The combination of the above studies, plus our ongoing research efforts in the area of molecular recognition, assembly, and catalysis, provide the fundamental tools for the rational design of artificial enzymes.
Nanochemistry. Hollow tubular structures, owing to their potential utility in a wide variety of chemical, biological, and materials science applications, lately have been the subject of considerable research. We have described the first example of a new class of tubular biomaterials termed "organic nanotubes." Cyclic disk-shaped subunits have been designed and shown to undergo chemically triggered self-assembly to produce open-ended tubular structures hundreds of nanometers long. Our general strategy allows for the design and synthesis of a wide range of tubular structures with specified internal diameters and surface characteristics. Tubular materials can now be designed to mimic biological channels and pore structures, study the physical and chemical properties of confined molecules, and control the growth and properties of inorganic clusters and biomineralization processes.
Self-Replicating Molecular Systems. Creating various self-replicating peptides is also a major goal of this lab. We have recently designed one self replicating system based on the leucine zipper motif of GCN4. One 32-residue alpha-helical peptide serves as a template to organize two constituent fragments in the proper orientation prior to ligation. Condensation of the two fragments produces a second template which can serve as a template for another such reaction.