Michael H. Hecht

photo of michael hecht
Associated Faculty, Chemistry
Frick Chemistry Laboratory, 330

Research Focus

Protein folding; design of novel proteins; molecular determinants of Alzheimer's disease
Research in the Hecht laboratory is focused in two areas. The first deals with the design of novel proteins 'from scratch.' The second is concerned with the molecular determinants of Alzheimer's disease.

Design of proteins de novo

The burgeoning field of proteomics explores the structures, functions, and interactions of the proteins encoded by living systems. As studies of natural proteins advance, one is tempted to look beyond proteomics: Rather than limiting our studies to the set of proteins existent on earth, we ask what structures and functions might be unobserved, but nonetheless possible. Studies that go beyond proteomics are motivated by a new question: Instead of asking "what exists?" we ask "what is possible?"

One way to answer this question is to construct and characterize libraries of proteins de novo. Such collections of non-biological biomolecules can then be examined against, and compared to, the evolutionarily selected (biological) proteins that currently exist.

We use combinatorial methods to devise libraries of novel proteins. Libraries of novel amino acid sequences can provide a rich source of diversity for the discovery of new proteins. However, randomly generated sequences will rarely fold into well-ordered protein-like structures. Therefore, to enhance the quality of a library, it is essential to ensure that combinatorial diversity be focused into those regions of 'sequence space' most likely to yield well-folded proteins. To accomplish this goal, we design the pattern of polar and nonpolar amino acids to favor structures containing abundant secondary structure (alpha-helices or beta-strands), while simultaneously burying hydrophobic side chains in the protein interior and exposing hydrophilic side chains to the surrounding solvent. Our methods combine rational design and combinatorial methods, and have enabled the construction of large libraries of de novo amino acid sequences that fold into well-ordered protein structures. Among our libraries of de novo proteins are alpha-helical structures, beta-sheet structures, proteins that bind cofactors (e.g. heme) and catalyze reactions, amyloid-like fibrils, self assembled monolayers, and prototypes for novel biomaterials. The 3D structure of one of our novel 4-helix bundles, as determined by NMR spectroscopy, is shown in the figure below. In accordance with the design, the polar side chains (red) are on the surface, while the nonpolar side chains (yellow) are buried in the protein interior.

Molecular determinants of Alzheimer's disease

The primary component of amyloid plaque in the brains of Alzheimer's patients is the 42-residue A-beta peptide. Although the amino acid sequence of A-beta is known, the molecular determinants of amyloidogenesis are not understood. To facilitate an unbiased search for the sequence determinants of A-beta aggregation, we developed a genetic screen that couples a readily observable phenotype in E. coli to the ability of a mutation in A-beta to reduce aggregation. Implementation of this screen enables the isolation of variants with reduced tendencies to aggregate. In future work, we plan to use this screen as a high throughput method for the discovery of novel pharmaceuticals that inhibit amyloidogenesis.

Further information can be found at www.princeton.edu/~hecht