Profile for Adrienne Loh

Research and publishing

Infectious diseases are the second leading cause of death worldwide and the third leading cause of death in economically advantaged countries. There is increasing evidence of persistent infections caused by microorganisms that are resistant to existing antibiotics, resulting in a serious threat to public health worldwide. Peptide antibiotics offer one promising solution because they act by perturbing cell membranes rather than acting on a specific protein target, making resistance more difficult to develop. Existing designed and natural peptide antibiotics tend to be helical in shape, and have both polar (hydrophilic) and non-polar (hydrophobic) regions. In my research program, we are trying to understand how to design peptide antibiotics with predictable structures, and to relate their structures to their lipid binding and cell-killing effectiveness. In particular, we are examining the roles of steric hindrance (“size”, “bulkiness”) and placement of charges (positive and/or negative) on helical structure.

Students in my group use a variety of methods to study these model peptide antibiotics. Some students use NMR spectroscopy to investigate the hydrogen-bonding networks by measuring H/D exchange kinetics or changes in amide proton chemical shift. Some students use NMR data to calculate the 3-dimensional structures of the peptides. Others use circular dichroism (CD) spectroscopy to monitor global structure or ITC (isothermal titration calorimetry) to measuring the thermodynamics of peptide-lipid binding. Soon to come are measurements of antimicrobial activity and cytotoxicity.

I am also interested in protein dynamics and the role that protein motions and conformation play in signal transduction. To this end, I have been working with R. Oswald at Cornell University, using NMR spectroscopy and isothermal titration calorimetry to study rote in-ligand binding interactions.

Selected Publications:

Martinez, M., Ahmed, A. H., Loh, A. P. Loh, and Oswald, R. E., (2014) Thermodynamics and Mechanism of the Interaction of Willardiine Partial Agonists with a Glutamate Receptor: Implications for Drug Development, Biochemistry, 53 (23), pp 3790–3795.

Ahmed, A. H., Thompson, M. D., Fenwick, M. E., Romero, B., Loh, A. P., Jane, D. E., Sondermann, H., Oswald, R. E. (2009). Mechanisms of Antagonism of the GluR2 AMPA Receptor: Structure and Dynamics of the Complex of Two Willardiine Antagonists with the Glutamate Binding Domain. Biochemistry, 48(18), 3894-3903.

Ahmed, A. H., Loh, A. P., Jane, D. E., Oswald, R. E. (2007). Dynamics of the S1S2 Glutamate Binding Domain of GluR2 Measured using 19F NMR Spectroscopy. J. Biol. Chem./ASBMB, 282(17), 12773-12784.

Oswald, R. E., Ahmed, A., Fenwick, M. K., Loh, A. P. (2007). Structure of Glutamate Receptors. in Current Drug Targets Current Drug Targets, 8, 573-582.

Adams, P. D., Loh, A. P., Oswald, R. E. (2004). Backbone Dynamics of an Oncogenic Mutant of Cdc42Hs shows Increased Flexibility at the Nucleotide Binding Site. Biochemistry, 43, 9968-9977.

Loh, A. P., Pawley, N., Nicholson, L. K., Oswald, R. E. (2001). An Increase in Sidechain Entropy Facilitates Effector Binding: NMR Characterization of the Methyl Group Dynamics in Cdc42Hs. Biochemistry/ACS, 40, 4590-4600.

Loh, A. P., Guo, W., Nicholson, L. K., Oswald, R. E. (1999). Backbone Dynamics of Inactive, Active, and Effector-Bound Cdc42Hs from Measurements of 15N Relaxation Parameters at Multiple Field Strengths. Biochemistry/ACS, 38, 12547-12557.