Faculty & Research
banner_research_labs

Michael H. Hecht

Associated Faculty, Chemistry

Michael Hecht

This email address is being protected from spambots. You need JavaScript enabled to view it.

Phone (609) 258-2901
locationFrick Lab, 330
Phone Lab (609) 258-2901
Faculty Assistant
Ilse DiMeglio
This email address is being protected from spambots. You need JavaScript enabled to view it.
Phone (609) 258-3962

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


Selected Publications

McKoy AF, Chen J, Schupbach T, Hecht MH. (2012) A novel inhibitor of Aβ peptide aggregation: from high throughput screening to efficacy in an animal model for Alzheimer's disease. J Biol Chem. 287: 38992-9000. Pubmed

Patel SC, Hecht MH. (2012) Directed evolution of the peroxidase activity of a de novo-designed protein. Protein Eng Des Sel. 25: 445-452. Pubmed

Das A, Wei Y, Pelczer I, Hecht MH. (2011) Binding of small molecules to cavity forming mutants of a de novo designed protein. Protein Sci. 20: 702-711. PubMed

Armstrong AH, Chen J, McKoy AF, Hecht MH. (2011) Mutations that replace aromatic side chains promote aggregation of the Alzheimer's Aβ peptide. Biochemistry. 50: 4058-4067 PubMed

Smith BA, Hecht MH. (2011) Novel proteins: from fold to function. Curr Opin Chem Biol. 15: 421-426. PubMed

Das A, Wei Y, Pelczer I, Hecht MH. (2011) Binding of small molecules to cavity forming mutants of a de novo designed protein. Protein Sci. 20: 702-711. PubMed

Fisher MA, McKinley KL, Bradley LH, Viola SR, Hecht MH. (2011) De novo designed proteins from a library of artificial sequences function in Escherichia coli and enable cell growth. PLoS One. 6: e15364. PubMed

Chen J, Armstrong AH, Koehler AN, Hecht MH. (2010) Small molecule microarrays enable the discovery of compounds that bind the Alzheimer's aβ Peptide and reduce its cytotoxicity. J Am Chem Soc. 132: 17015-17022. PubMed

Patel SC, Bradley LH, Jinadasa SP, Hecht MH. (2009) Cofactor binding and enzymatic activity in an unevolved superfamily of de novo designed 4-helix bundle proteins. Protein Sci. 18: 1388-1400. PubMed

Go A, Kim S, Baum J, Hecht MH. (2008) Structure and dynamics of de novo proteins from a designed superfamily of 4-helix bundles. Protein Sci.17: 821-832. PubMed

Kim W, Hecht MH. (2008) Mutations enhance the aggregation propensity of the Alzheimer's A{beta} peptide. J Mol Biol. 377: 565-574. PubMed

Das A, Hecht MH. (2007) Peroxidase activity of de novo heme proteins immobilized on electrodes. J Inorg Biochem. 101: 1820-1826. PubMed

Kim W, Kim Y, Min J, Kim DJ, Chang YT, Hecht MH. (2006) A high-throughput screen for compounds that inhibit aggregation of the Alzheimer's peptide. ACS Chem Biol 1: 461-469. PubMed

Bradley LH, Wei Y, Thumfort P, Wurth C, Hecht MH. (2006) Protein design by binary patterning of polar and nonpolar amino acids. Methods Mol Biol 352: 155-166. PubMed

Kim W, Hecht MH. (2006) Generic hydrophobic residues are sufficient to promote aggregation of the Alzheimer's A{beta}42 peptide. Proc Natl Acad Sci 103: 15824-15829. PubMed

Bradley LH, Thumfort PP, Hecht MH. (2006) De novo proteins from binary-patterned combinatorial libraries. Methods Mol Biol 340: 53-69. PubMed

Das A, Trammell SA, Hecht MH. (2006) Electrochemical and ligand binding studies of a de novo heme protein. Biophys Chem 123: 102-112. PubMed

Klepeis JL, Wei Y, Hecht MH, Floudas CA. (2005) Ab initio prediction of the three-dimensional structure of a de novo designed protein: a double-blind case study. Proteins 58: 560-570. PubMed

Wurth C, Kim W, Hecht MH. (2006) Combinatorial approaches to probe the sequence determinants of protein aggregation and amyloidogenicity. Protein Pept Lett 13: 279-286. PubMed

Kim W, Hecht MH. (2005) Sequence determinants of enhanced amyloidogenicity of Alzheimer A{beta}42 peptide relative to A{beta}40. J Biol Chem 280: 35069-35076. PubMed

Hu Y, Das A, Hecht MH, Scoles G. (2005) Nanografting de novo proteins onto gold surfaces. Langmuir 21: 9103-9109. PubMed

Bradley LH, Kleiner RE, Wang AF, Hecht MH, Wood DW. (2005) An intein-based genetic selection allows the construction of a high-quality library of binary patterned de novo protein sequences. Protein Eng Des Sel 18: 201-207. PubMed

Hecht MH, Das A, Go A, Bradley LH, Wei Y. (2004) De novo proteins from designed combinatorial libraries. Protein Sci. 13: 1711-1723. PubMed

Wei Y, Hecht MH. (2004) Enzyme-like proteins from an unselected library of designed amino acid sequences. Protein Eng Des Sel 17: 67-75. PubMed

Wei Y, Kim S, Fela D, Baum J, Hecht MH. (2003) Solution structure of a de novo protein from a designed combinatorial library. Proc Natl Acad Sci USA 100: 13270-13273. PubMed

Wei Y, Liu T, Sazinsky SL, Moffet DA, Pelczer I, Hecht MH. (2003) Stably folded de novo proteins from a designed combinatorial library. Protein Sci 12: 92-102. PubMed

Wurth C, Guimard NK, Hecht MH. (2002) Mutations that reduce aggregation of the Alzheimer's Abeta42 peptide: an unbiased search for the sequence determinants of Abeta amyloidogenesis. J Mol Biol 319: 1279-1290. PubMed

Brown CL, Aksay IA, Saville DA, Hecht MH. (2002) Template-directed assembly of a de novo designed protein. J Am Chem Soc 124: 6846-6848. PubMed

Kamtekar S, Schiffer JM, Xiong H, Babik JM, Hecht MH. (1993) Protein design by binary patterning of polar and nonpolar amino acids. Science 262: 1680-1685. PubMed

MolBio Events

Mon, Apr 21, 2014

Wed, Apr 23, 2014

Thu, Apr 24, 2014

Fri, Apr 25, 2014

Contact Us

Lewis Thomas Laboratory at Princeton University

119 Lewis Thomas Laboratory
Washington Road, Princeton, NJ  08544-1014

Tel: (609) 258-3658
Fax: (609) 258-3980
Website:  molbio.princeton.edu