Proteins: Design, Recognition, Function and Characterization

The investigation, control and mimicry of protein structure and function form the third theme of Yale’s Graduate Studies in Chemical Biology. Proteins occupy the central position in the machinery of the living cell by providing a diverse and robust framework for the display of a wide range of reactivities and functions. In this regard the study of protein function provides many potential points where the chemical and biological training of students intersects. Researchers at Yale have established a strong series of research programs focused on protein structure and function and also an extensive network of collaborations that expose students to concepts and techniques in Chemical Biology.

Karen Anderson (Pharmacology) investigates enzymatic reactions and receptor-ligand interactions at a molecular level. Her approach is to use a combination of kinetic and structural techniques including rapid transient kinetics (stopped-flow fluorescence and rapid chemical quench methodologies), NMR, and X-Ray crystallography. This allows a quantitative and structural basis for understanding how proteins work at a molecular level.

Richard Baxter (Chemistry) studies the innate immune system of insects that are vectors of human disease, using structural, biophysical and biochemical methods. Efforts to understand the molecular basis of the innate immune response are coupled with the development of novel chemical entities targeting the immune system, including both cell-based and in vitro high-throughput screening.

Demetrios Braddock (Pathology) is interested in the structural biology of proteins involved in human malignancy. Active projects in his lab are studies on protein:DNA complexes that regulated the c-myc oncogene, and the structure determination, mechanism of action, kinetics, and small molecule inhibition of inhibition of enzymes with stimulate angiogenesis and tumor metastasis.

Craig Crews (MCDB) explores novel mechanisms in cell biology using a combination of chemical and biochemical approaches. This strategy has been referred to as “chemical genetics”, whereby biologically active natural products are used as molecular proves for the exploration of cell biology.

Enrique de la Cruz (MB&B) studies the molecular basis of free-energy coupling in non-muscle myosins using an interdisciplinary approach that combines biochemistry, biophysics and molecular biology to relate the dynamics (kinetics), energetics (thermodynamics) and conformations (structures) of biochemical intermediates in the energy transduction pathway.

William Jorgensen (Chemistry) is developing and using computational methods to make quantitative predictions on the structure, energetics, and reactivity of biomolecular systems. His theoretical approach centers on computer simulations of the biomolecular systems at the atomic level with explicit inclusion of the solvent.

Elias Lolis (Pharmacology) also studies protein structure. Using X-ray crystallography, his lab determines the three-dimensional structure of proteins to gain a better understanding the molecular mechanism by which they exert their biological effects. Proteins currently under study include several cytokines such as SDF-1, MIP-II, and macrophage migration inhibitory factor (MIF).

Patrick Loria (Chemistry) focuses on understanding how the dynamic and structural properties of enzymes correlate with their function. This is accomplished by primarily with NMR spectroscopy but complemented by chemical biophysical techniques.

Yorgo Modis (MB&B) studies how receptors of the innate immune system recognize various microbial structural motifs. The Modis lab also seeks to understand how flaviviruses use their envelope protein to enter cells. The overall goal is to guide the rational design of biologics and small molecules that modulate innate immune signaling or inhibit viral entry.

Lynne Regan (MB&B) is interested in the design and characterization of proteins with novel ligand binding activities. These studies hold great promise for development in many areas, such as the development of novel bioelectrical materials and biosensors through surface immobilization.

Elizabeth Rhodes (Molecular Biophysics & Biochemistry) studies protein folding and aggregation as related to the pathology of Parkinson’s and Alzheimer’s diseases.  The primary experimental methods she uses are single molecule fluorescence and fluorescence correlation spectroscopy, augmented by computational tools.

Alanna Schepartz (Chemistry) research interests also include novel protein design . Her lab explores a general strategy that is referred to as “protein grafting” for the design of folded, miniature proteins that bind receptors (other proteins or DNA) that themselves bind a-helices. The goal is to understand how to balance the requirements of folding and recognition to generate the smallest possible molecule that retains biological activity.

Matthew Simon studies chromatin and large non-coding RNAs (1ncRNAs).  Many of the projects in his lab include technology development, and use approaches from protein engineering, synthetic chemistry, nucleoside biochemistry, molecular biology and genomics to investigate the molecules that regulate our genomes.

Yong Xiong (Pharmacology) .

Elsa Yan (Chemistry) studies G protein-coupled receptors (GPCRs). GPCRs belong to the largest gene family in the human genome. They are important drug targets. The Yan group develop methods of using Nanodiscs to purify GPCRs in lipid membrane environments and using unnatural amino acid mutagenesis to label GPCRs with spectroscopic probes. These methods enable molecular studies of GPCRs with biophysical spectroscopy. These studies reveal the activation mechanism of GPCRs, providing insight into rational drug design targeting GPCRs. .