Special Seminar
Thursday, January 22, 2015

11:15 AM  112 KLB

Insights into dynamic biomolecules and drug compounds derived from NMR spectroscopy
Dr. Pieter E. S. Smith

Abstract:

It is increasingly being appreciated that dynamics play an important role in biomolecules’ function and
dysfunction. NMR spectroscopy has evolved into a powerful technique for obtaining quantitative
measurements of the conformational flexibility and structural features of dynamic biomolecules. A
variety of biomolecular NMR investigations are presented to demonstrate the versatility and strength of
this approach, notably including studies centering on human Islet Amyloid PolyPeptide (IAPP), which
is associated with type 2 adult-onset diabetes, and studies centering on a huntingtin exon-1 fragment
(Htt), which is responsible for Huntington’s disease. Because IAPP is a highly amyloidogenic peptide,
it has been suggested that the formation of amyloid fibers is responsible for its cytotoxic disruption of
insulin-producing β-cell membranes. Utilizing a variety of model IAPP peptides and peptide fragments,
we showed that the cytotoxicity of model peptides, including those not ordinarily prone to aggregation,
correlates to their ability to induce negative curvature in lipid bilayers [1]. More recent investigations in
the Frydman lab have focused on the huntingtin amyloid protein responsible for Huntington’s disease.
Its exon-1 fragment, which consists of the first 17 N-terminal residues and an adjacent polymorphic
glutamine tract, is the primary culprit in the development of the disease. We have characterized the
dynamics and structure of this fragment and efforts are underway to construct a map of regions of the
fragment associating with various mouse brain-derived cytosolic extracts, which are prepared by
differential centrifugal sedimentation. Additionally, a variety of NMR methods developed and applied
in the Frydman and Ramamoorthy labs to study transiently formed biomolecular structures, protein
dynamics, and pharmaceutical compounds are presented. These include the Dark-state Exchange
Saturation Transfer (DEST) [2], Selective Dynamical Recoupling (SDR) [3], Time-Optimized FouriEr
Encoding (TOFEE) [4], and Ultrafast Inversion Recovery (UFIR) [5] methods.
1. Smith, PES, Brender, JR, and Ramamoorthy, A. J. Am. Chem. Soc. 131 (2009) 4470-4478.
2. Fawzi, NL et al. Nat. Protoc. 7 (2012) 1523-1533.
3. Smith, PES et al. Proc. Natl. Acad. Sci. U. S. A. 109 (2012) 5958-5961.
4. Zhang, Z, Smith PES, and Frydman, L. J. Chem. Phys. 141 (2014) 194201.
5. Smith, PES et al. ChemPhysChem. 14 (2013) 3138-3145.