Professor of Chemistry
Frick Laboratory, 330
Nagwan I. Ali
Frick Laboratory, 128
Research in the Hecht group focuses in two areas: Synthetic Biology and Alzheimer’s Disease. Although these fields may seem quite different, they explore two facets of the same problem. Synthetic biology requires an ability to devise novel proteins, which ultimately comes down to designing amino acid sequences that fold into a specific 3-dimensional structure. Conversely, probing the molecular underpinnings of Alzheimer’s disease requires an understanding of how sequences fail to fold into globular protein structures, but instead misfold into oligomeric or fibrillar structures.
(1) Synthetic Biology: From Protein Design to Artificial Genomes. Research in the life sciences has advanced to a point where we can consider the possibility of sustaining life using molecular parts that did not evolve in nature, but which are designed and synthesized in the laboratory. Although myriad forms of life evolved over billions of years, the biosphere has sampled only a miniscule fraction of the possible genes and proteins that could be constructed. Are these biologically selected sequences somehow special? Or is it possible to sustain life using a ‘molecular parts kit’ designed de novo? Our research addresses these questions by going beyond the limited collection sampled by nature; beyond what exists (or existed in the past) in living systems. We explore artificial biological information (genes) and macromolecules (proteins) to probe the ability of these novel genes and proteins to perform biochemical activities, and ultimately to sustain life.
Our work in synthetic biology is enabled by methods we developed to design and construct combinatorial libraries of novel proteins that fold into stable structures. With collections of millions of well-folded de novo proteins, we explore a range of questions at the interface of chemistry and biology For example, we can test the chemical and structural requirements for protein design, while also probing the biological implications of proteome design. Moreover, because our designed proteins are expressed from synthetic genes cloned into living cells, we can begin to construct ‘artificial genomes’ comprising sequences (genes and proteins) that never existed before in biology. Recent results show that these novel macromolecules – which bear no resemblance to natural genes or proteins – can provide some of the functions necessary to enable cell growth.
Thus, the molecular ‘parts kit’ for life need not be limited to genes and proteins derived nature; and artificial genomes capable of sustaining life may soon be within reach.
(2) Alzheimer’s disease: Molecular Underpinnings and the Search for New Therapeutics. One hundred years ago Alois Alzheimer observed a relationship between cognitive impairment and the presence of plaque in the brains of patients suffering from the disease that now bears his name. The plaque was subsequently shown to be composed primarily of a protein fragment, or peptide, called Aβ. It is now understood that aggregation of Aβ into oligomers and amyloid fibrils plays a central role in the molecular etiology of Alzheimer’s disease (AD). Our work on AD aims to address two questions: (i) What causes Aβ aggregation? and (ii) Can we block it? Our research on the causes of Aβ aggregation focuses on the relationship between the sequence of Aβ and its propensity to aggregate. We constructed collections of mutant Aβ peptides and characterized which features of the sequence enhance or prevent aggregation. Our search for Alzheimer’s therapeutics relies on a novel high throughput screen for compounds that inhibit aggregation of the A-beta peptide. Several promising compounds have been isolated, and are being tested in animal models.
Whitaker Foundation Young Investigator Award (1992)
Beckman Young Investigator Award (1993)
Protein Society – Kaiser Award (2003)
Cherny, I.; Korolev, M.; Koehler, A. N.; Hecht, M. H., “Proteins from an Unevolved Library of de novo Designed Sequences Bind a Range of Small Molecules.” Acs Synthetic Biology 2012, 1 (4), 130-138.
Patel, S. C.; Hecht, M. H., “Directed evolution of the peroxidase activity of a de novo-designed protein.” Protein Engineering Design & Selection 2012, 25 (9), 445-451.
Arai, R.; Kobayashi, N.; Kimura, A.; Sato, T.; Matsuo, K.; Wang, A. F.; Platt, J. M.; Bradley, L. H.; Hecht, M. H., “Domain-Swapped Dimeric Structure of a Stable and Functional De Novo Four-Helix Bundle Protein, WA20.” Journal of Physical Chemistry B 2012, 116 (23), 6789-6797.
McKoy, A. F.; Chen, J.; Schupbach, T.; Hecht, M. H., “A Novel Inhibitor of Amyloid beta (A beta) Peptide Aggregation from high throughput screening to efficacy in an animal model of Alzheimer disease .” Journal of Biological Chemistry 2012, 287 (46), 38992-39000.
Fisher, M. A.; McKinley, K. L.; Bradley, L. H.; Viola, S. R.; Hecht, M. H., “De Novo Designed Proteins from a Library of Artificial Sequences Function in Escherichia Coli and Enable Cell Growth.” Plos One 2011, 6 (1).
Das, A.; Wei, Y.; Pelczer, I.; Hecht, M. H., “Binding of small molecules to cavity forming mutants of a de novo designed protein.” Protein Science 2011, 20 (4), 702-711.
Armstrong, A. H.; Chen, J.; McKoy, A. F.; Hecht, M. H., “Mutations That Replace Aromatic Side Chains Promote Aggregation of the Alzheimer’s A beta Peptide.” Biochemistry 2011, 50 (19), 4058-4067.
Olzscha, H.; Schermann, S. M.; Woerner, A. C.; Pinkert, S.; Hecht, M. H.; Tartaglia, G. G.; Vendruscolo, M.; Hayer-Hartl, M.; Hartl, F. U.; Vabulas, R. M., “Amyloid-like Aggregates Sequester Numerous Metastable Proteins with Essential Cellular Functions.” Cell 2011, 144 (1), 67-78.
Chen, J.; Armstrong, A. H.; Koehler, A. N.; Hecht, M. H., “Small Molecule Microarrays Enable the Discovery of Compounds That Bind the Alzheimer’s A beta Peptide and Reduce its Cytotoxicity.” Journal of the American Chemical Society 2010, 132 (47), 17015-17022.
Patel, S. C.; Bradley, L. H.; Jinadasa, S. P.; Hecht, M. H., “Cofactor binding and enzymatic activity in an unevolved superfamily of de novo designed 4-helix bundle proteins.” Protein Science 2009, 18 (7), 1388-1400.
Go, A.; Kim, S.; Baum, J.; Hecht, M. H., “Structure and dynamics of de novo proteins from a designed superfamily of 4-helix bundles.” Protein Science 2008, 17 (5), 821-832.
Kim, W.; Hecht, M. H., “Mutations enhance the aggregation propensity of the Alzheimer’s A beta peptide.” Journal of Molecular Biology 2008, 377 (2), 565-574.
Das, A.; Hecht, M. H., “Peroxidase activity of de novo heme proteins immobilized on electrodes.” Journal of Inorganic Biochemistry 2007, 101 (11-12), 1820-1826.
Kim, W.; Kim, Y.; Min, J.; Kim, D. J.; Chang, Y.-T.; Hecht, M. H., “A high-throughput screen for compounds that inhibit aggregation of the Alzheimer’s peptide.” Acs Chemical Biology 2006, 1 (7), 461-469.
Wurth, C.; Kim, W.; Hecht, M. H., “Combinatorial approaches to probe the sequence determinants of protein aggregation and amyloidogenicity.” Protein and Peptide Letters 2006, 13 (3), 279-286.
Kim, W.; Hecht, M. H., “Generic hydrophobic residues are sufficient to promote aggregation of the Alzheimer’s A beta 42 peptide.” Proceedings of the National Academy of Sciences of the United States of America 2006, 103 (43), 15824-15829.
Das, A.; Trammell, S. A.; Hecht, M. H., “Electrochemical and ligand binding studies of a de novo heme protein.” Biophysical Chemistry 2006, 123 (2-3), 102-112.
Hu, Y.; Das, A.; Hecht, M. H.; Scoles, G., “Nanografting de novo proteins onto gold surfaces.” Langmuir 2005, 21 (20), 9103-9109.
Kim, W.; Hecht, M. H., “Sequence determinants of enhanced amyloidogenicity of Alzheimer A beta 42 peptide relative to A beta 40.” Journal of Biological Chemistry 2005, 280 (41), 35069-35076.
Hecht, M. H.; Das, A.; Go, A.; Bradley, L. H.; Wei, Y. N., “De novo proteins from designed combinatorial libraries.” Protein Science 2004, 13 (7), 1711-1723.
Wei, Y. N.; Hecht, M. H., “Enzyme-like proteins from an unselected library of designed amino acid sequences.” Protein Engineering Design & Selection 2004, 17 (1), 67-75.
Wei, Y. N.; Kim, S.; Fela, D.; Baum, J.; Hecht, M. H., “Solution structure of a de novo protein from a designed combinatorial library.” Proceedings of the National Academy of Sciences of the United States of America 2003, 100 (23), 13270-13273.
Brown, C. L.; Aksay, I. A.; Saville, D. A.; Hecht, M. H., “Template-directed assembly of a de novo designed protein.” Journal of the American Chemical Society 2002, 124 (24), 6846-6848.
Xu, G. F.; Wang, W. X.; Groves, J. T.; Hecht, M. H., “Self-assembled monolayers from a designed combinatorial library of de novo beta-sheet proteins.” Proceedings of the National Academy of Sciences of the United States of America 2001, 98 (7), 3652-3657.
Moffet, D. A.; Certain, L. K.; Smith, A. J.; Kessel, A. J.; Beckwith, K. A.; Hecht, M. H., “Peroxidase activity in heme proteins derived from a designed combinatorial library.” Journal of the American Chemical Society 2000, 122 (31), 7612-7613.