The Center for Computational and Integrative Biologywill be hosting Dr. Neal Zondlo, Professor in the Department of Chemistry and Biochemistry at the University of Delaware.  

Dr. Zondlo will be speaking on the following topic:

Title: Insights into the nature of aromatic interactions and structural effects of protein post-translational modifications

Abstract Aromatic residues, proline residues, and post-translational modifications have important roles in protein structure and function. We investigated the control protein structure via aromatic interactions and via post-translational modifications. Aromatic interactions with C–H bonds (C–H/? interactions) are commonly observed in protein structure, protein-protein interactions, carbohydrate recognition, drug binding, and biomaterials. In proteins, C–H/? interactions are particularly observed between aromatic residues and proline or glycine, including at biomolecular interfaces and within membranes. C–H/? interactions are strongest with polarized C–H bonds, leading to their description as analogous to cation/? interactions, with additional contributions in water from the hydrophobic effect. We have examined the fundamental nature of C–H/? and S–H/? interactions using designed peptides and analysis by NMR spectroscopy, x-ray crystallography, IR spectroscopy, DFT calculations, and bioinformatics analysis. Across 50 peptides, the strength of the aromatic-proline C–H/? interaction was observed to be dependent on the electronics of the aromatic ring, with the strongest interactions with the most electron-rich aromatic rings. Stronger C–H/? interactions were associated with more favorable enthalpy and more unfavorable entropy. In contrast to either a primarily electrostatic basis for the C–H/? interaction or the hydrophobic effect, these interactions exhibited similar enthalpies and similar dependence on aromatic electronic properties in water and in protic or aprotic organic solvents. The crystal structure of Boc-Trp-flp-NHMe revealed a type VIa1 ?-turn conformation with a short C–H…Caromatic distance of 2.51 Å, well below the 2.9 Å sum of the van der Waals radii of H and C. The C–H bond in this close C–H/? interaction was directed toward the carbons of the aromatic ring, in contrast to the preference for the centroid of the aromatic ring observed in cation/? interactions. PDB and CSD analysis revealed similar trends, with short H…C through-space distances (as close as 2.3 Å) associated with interactions at the carbons, rather than the centroid of the aromatic ring. S–H/? interactions involving cysteine have been implicated in stabilization of protein structures, but are not well described due to a lack of structural data on thiol geometries with aromatic rings. The crystal structure of Boc-4-SH-Phe-OtBu exhibited a short intermolecular S–H/? interaction of 2.63 Å, with similar geometries as observed in C–H/? interactions. DFT calculations revealed substantial stabilizing molecular orbital overlap between the C–H or S–H ?* LUMO and the aromatic ? HOMO. These results suggest a primarily molecular orbital overlap (stereoelectronic) basis for the strongest C–H/? and S–H/? interactions. These results have substantial implications for the modeling of interactions with aromatic groups. In addition, serine/threonine phosphorylation and O-GlcNAcylation are central to signal transduction. We examined the structural effects of serine versus threonine phosphorylation and O-GlcNAcylation in two general peptide contexts, at Ser/Thr-Pro motifs in natively disordered peptides and within alanine-rich ?-helical model peptides. Using CD and NMR spectroscopy, we found that the structural effects of threonine phosphorylation were greater than those of serine phosphorylation in all peptide contexts examined, with phosphorylation inducing polyproline helix in a proline-rich context or functioning as an inducible start or stop signal in ?-helices, with phosphothreonine at the N-terminus the most helix-stabilizing residue and phosphothreonine in the interior of an ?-helix inducing a random coil. Phosphorylation of the tau protein results in a significant disorder-to-order transition, with implications in mechanisms of Alzheimer’s disease and CTE.

For more information about Dr. Zondlo you can visit his webpage at:

Seminar will be Tuesday, November 15, 2016 at 12:20pm in the Science Lecture Hall.