Professor of Chemistry
Ph.D. Northwestern University, 1967
(Biophysical, Biorganic, and Medicinal Chemistry)
Research in the Andersen group focuses on both the fundamental thermodynamics and structural features associated with biorecognition phenomena and practical applications in drug and protein design. The primary biophysical tools employed are spectroscopic: NMR determinations of polypeptide structure and dynamics, IR- and fluorescence-monitored T-jump kinetics for folding pathways, CD studies of the melting of secondary and tertiary structure. Drug design efforts are supported by NMR structural data for protein hormones and enzymes for key steps required for the viability of bacteria. Active programs in mutant protein over-expression, peptide synthesis, and combinatorial synthesis of small molecule inhibitor libraries support this effort. Illustrative projects are briefly outlined in the following paragraphs.
The earliest stages of protein folding are studied using a priori designed helices and beta hairpins with specific labeling patterns that allow the definition of the thermodynamics, kinetics, and pathways of structuring using NMR and T-jump methods. These studies have already determined the time scales of helix (200 ns) and hairpin (4 – 10 µs) formation and have established that helix formation, but not sheet formation, occurs too rapidly to contribute during the rapid hydrophobic collapse phase of protein folding. The mechanistic details of secondary structure formation are currently being addressed.
‘Minimalist’ proteins (< 25 residues) that display the diagnostic folding features of much larger native proteins are being designed. These systems should provide an atom-level understanding of the factors that yield stable protein folds and are small enough to allow for computational simulations that can be experimentally tested. To date, fully cooperative folding driven by the hydrophobic effect has been realized with systems as small as 18 residues and fully folded systems with protected amide and hydroxyl protons as small as 8 residues have been designed.
The minimalist protein constructs also provide scaffolds for pharmacophore display for drug discovery. They have significant advantages over random peptide libraries in that the three dimensional display of the binding moieties is certain due to the defined fold. Recent studies have established that designed hairpin bearing aromatic sidechains can inhibit amyloid fibril formation, a key step in many “protein folding diseases."
Potent, selective inhibitors of the LpxC enzyme of Pseudomonas aeruginosa (and other gram negative pathogens) are viewed as a potential medicinals for treating resistant hospital acquired infections and the common infections in the lungs of cystic fibrosis patients. Very potent lead compounds have been prepared using combi-synthesis libraries with design optimization based on bioassays and fluorine NMR assays of the relative affinities of leads to the native enzyme.
Folding Landscape Exploration by Capping b Structures and Circular Permutation, B. Kier, A. Byrne, J. Anderson, M. Scian, I. Shu & N. H. Andersen, 32ndt EPS Symp. Vol., in press.
Probing Alpha-Synuclein Molecular Binding Sites and their Effects on Aggregation by NMR Spectroscopy, A.Byrne, M. Bisaglia, L. & N. H. Andersen, 32ndt EPS Symp. Vol., in press.
Crystal and NMR structures of a Trp-cage mini-protein benchmark for computational fold prediction, M. Scian, J. C. Lin, I. Le Trong, G. I. Makhatadze, R. E. Stenkamp & N. H. Andersen, Proc. Natl. Acad. Sci. USA, 109, in press (2012).
Designed Hairpin Peptides Interfere with Amyloidogenesis Pathways: Fibril Formation and Cytotoxicity Inhibition, Interception of the Preamyloid State, K. N. L. Huggins, M. Bisaglia, L. Bubacco, M. Tatarek-Nossol, A. Kapurniotu & N. H. Andersen, Biochemistry, 50, 8202-8212 (2011).
Concerning the Optimal Salt Bridge for Trp-cage Stabilization, D. V. Williams, A. Byrne, J. M. Stewart & N. H. Andersen, Biochemistry, 50, 1143-1152 (2011).
β-Sheet 13C Structuring Shifts Appear only at the H-bonded Sites of Hairpins, I. Shu, J. M. Stewart, M. Scian, B. L. Kier & N. H. Andersen, J. Am. Chem. Soc., 133, 1196-1199 (2011).
Designed Hairpins Modulate the Amyloidogenesis of a Synuclein: Oligomerization Inhibition and Diversion to Non-amyloid Aggregates, N. H. Andersen, K. N. L. Huggins, M. Bisaglia & L. Bubacco, 31st EPS Symp. Vol., 22-23 (2010).
Stabilizing Capping Motif for β Hairpins and Sheets, B. L. Kier, I. Shu, L. A. Eidenschink & N. H. Andersen, Proc. Natl. Acad. Sci. USA, 107, 10466-10471 (2010).
Terminal side-chain packing of a designed β-hairpin influences its conformation and stability, L. Eidenschink, E. Crabbe & N. H. Andersen, Biopolymers, 91, 557-564 (2009).
Solution-state Structures of Human Pancreatic Amylin and Pramlintide, J. R. Cort, Z. Liu, G. M. Lee, K. N. L. Huggins, S. Janes, K. Prickett & N. H. Andersen, Protein Engineering Design and Selection, 22, 497-513 (2009).
Development of Calcitonin Salmon Nasal Spray: Similarity of peptide formulated in chlorobutanol compared to benzalkonium chloride as preservative, H. R. Costantino, H. Culley, L. Chen, D. Morris, M. Houston, S. Roth, M. J. Phoenix, C. Foerder, J. S. Philo, T. Arakawa, L. A. Eidenschink, N. H. Andersen, G. Brandt & S. C. Quay, J. Pharmaceutical Sciences, 98, 3691-3706 (2009).
Very Short Peptides with Stable Folds: Building on the Inter-relationship of Trp/Trp, Trp/cation, and Trp/backbone-amide Interaction Geometries, L. A. Eidenschink, B. L. Kier, K. Huggins & N. H. Andersen, Proteins: Structure, Function & Bioinformatics, 75, 308-322 (2009).