Symposium Speakers

 

 

 

 

 

 

 

 

 

 

 

 

 

Plenary Speaker

Dorothee Kern
Professor of Biochemistry
Investigator, Howard Hughes Medical Institute
Brandeis University
Waltham, MA

NMR at its Best: Evolution of Protein Dynamics over 3.5 Billion Years and New Strategies for Drug Design

As a direct manifestation of molecular kinetic energy, temperature is a fundamental evolutionary driver for chemical reactions. However, it is currently not understood how the natural evolution of catalytic efficiency responds to dramatic changes in environmental temperatures. Using Ancestral Sequence Reconstruction (ASR) we resurrect and biophysically characterize the oldest common ancestral kinase and enzymes along the evolutionary path to modern kinases. Strikingly, enzymes coped with an inherent drop in catalytic speed caused as the earth cooled down over 3.5 billion years by accelerating protein dynamics and adapting thermostability by unexpected mechanisms, as characterized by NMR (1). In the second part of my talk I discuss novel and unconventional ideas for rational drug design based on protein dynamics and protein evolution.

(1) V. Nguyen, C. Wilson, M. Hoemberger, J. Stiller, R. Agafonov, J. English, S. Kutter, D. Theobald and D. Kern “Evolutionary Drivers of Thermoadaptation in Enzyme Catalysis” Science 2017

Paul Adams

 

 

 

 

 

 

 

 

 

 

 

 

Paul Adams
Associate Professor of Biochemistry, Cellular and Molecular Biology
University of Arkansas
Fayetteville, AR

Biochemical and Biophysical Approaches to Characterize the Molecular Basis of Abnormal Cell Signaling Function Involving Ras-Related Proteins

Ras proteins are often mutated in many human cancers, making them excellent protein models to probe structure-function relationships of cell-signaling processes mediating cell transformation. Target-based approaches to avert Ras-stimulated abnormal signal transduction should be enhanced by a better understanding of the structural biology of Ras-related Protein-Protein Interactions (PPIs), as well as, protein function. Cell division cycle 42 (Cdc42) is the model Ras protein being studied by this laboratory. Mutations as well as PPIs play a significant role in Cdc42-stimulated cell signaling. As such, the goals of this research are to understand key factors, using biophysical and biochemical techniques and approaches, which underlie the molecular basis of Cdc42 activity. Our central hypothesis is that there are unique structural and dynamic features of Cdc42 that can be exploited to modulate protein interactions and influence abnormal cell signaling activity. Recent results in this regard will be presented.

 

 

 

 

 

Ernesto Fuentes
Associate Professor of Biochemistry
University of Iowa
Carver College of Medicine
Iowa City, IA

Insights into Molecular Recognition from PDZ Domains

Molecular recognition is critical for the function and regulation of signal transduction in all cell types. PSD-95/Dlg1/ZO-1 (PDZ) domains are among the most abundant protein-protein interaction modules in the human proteome, commonly found in multi-domain signal scaffolding proteins. PDZ domains typically recognize a variety of short amino acid motifs, including the C-termini and internal peptide sequences of partner proteins. How PDZ domains accommodate these diverse interaction partners while providing specificity remains poorly understood. The overall goal of our studies is to define the molecular basis underlying PDZ domain specificity towards its known ligands. In this presentation, I will discuss recent studies using several model PDZ domains that reveal how specificity is obtained in for model PDZ domains that bind C-terminal and internal peptide sequences. In addition, I will provide examples for how conformational dynamics and structure contribute to molecular recognition.

Lorieau NMR

 

 

 

Justin Lorieau
Assistant Professor of Chemistry
University of Illinois at Chicago
Chicago, IL

Hybrid NMR: A Combination of Solution and Solid-State NMR

We present Hybrid NMR, a new research tool that combines the detailed information content of the anisotropic Hamiltonian of solid-state NMR with the high resolution of solution NMR. Hybrid NMR uses crystalline hydrogel samples to measure chemical shift anisotropy (CSA) or dipolar tensors in small molecules or relatively large biomolecules. We demonstrate the application of Hybrid NMR in measuring CSA tensors in a small molecule. We further show how new theory and pulse sequences can be used to determine anisotropic dynamic maps of molecules. These maps reveal the molecular dynamics of biomolecules, which gives useful new information on the function of proteins.

 

Aaron Rossini

 

 

 

 

 

 

Aaron Rossini
Assistant Professor of Chemistry
Iowa State University
Ames, IA

Sensitizing Solid-State NMR Spectroscopy for the Characterization of Pure and Formulated Pharmaceuticals

Solid-state NMR spectroscopy is routinely applied for the characterization of active pharmaceutical ingredients (APIs) in both pure and dosage forms. However, solid-state NMR experiments on many APIs suffer from poor sensitivity because many crystalline organic solids possess very long proton longitudinal relaxation times. Furthermore, 13C solid-state NMR experiments on dosage forms of APIs are challenging since the 13C NMR signals from the API often overlaps with those from the excipient and the loading levels of the APIs are often very low (1-10 wt.%). In this contribution, I will describe how dynamic nuclear polarization (DNP) enhanced solid-state NMR can be applied to “ordinary” micro-particulate organic solids (such as APIs) and how DNP addresses the issues of long proton T1, signal overlap and dilution in formulated APIs. DNP enhanced solid-state NMR can also be applied to determine the protonation states of APIs in salts and cocrystals.