Conformational Chemistry of Macromolecules at the Cell Membrane

Wednesday, March 8, 2017

3:30 p.m. Room 1005 Haworth

Dr. Christopher Neale

Center for Nonlinear Studies, Los Alamos National Laboratory

Conformational Chemistry of Macromolecules at the Cell Membrane

Macromolecules frequently associate in living cells and tissues, where specific binding interactions regulate molecular localization and activity. These interactions depend not only on molecular identity, but also, crucially, on molecular structure (i.e., conformation). Some macromolecules are constrained to a few distinct conformational states whose large intervening free energy barriers lead to switch-like behavior analogous to a reversible chemical reaction. Other macromolecules exhibit more complex dynamics in which many functionally distinct conformations rapidly interconvert across relatively small energetic barriers. G protein-coupled receptors (GPCRs) are signaling proteins of the later type. Strategically located at the cellular periphery, these membrane proteins transmit extracellular information into the cell. The complex free energy landscapes of GPCRs enable the integration of multiple simultaneous inputs and provision a diverse range of signaling outputs. The human genome contains over 800 GPCRs, which have evolved to bind thousands of different chemicals and instigate a wide array of cellular responses. As such, GPCRs are targeted by 30% of drugs and play central roles in vision, appetite, mood, heart rate, blood pressure, and pain control. However, it is unclear how these receptors achieve robust signaling from active states that appear to be short-lived. To resolve this apparent contradiction, I will show how signaling can be regulated by specific interactions between these receptors and lipids from their native environment. I will also show how free energy landscapes underling protein-protein interactions and folding upon binding can be used to predict the interactions between GPCRs and downstream signaling proteins. Collectively, this research uses molecular dynamics simulations and cutting-edge enhanced-sampling simulation techniques to provide new understandings of GPCR function in native environments, a crucial step in defining how these druggable receptors work.

BIO: Chris Neale received his PhD in Biochemistry from the University of Toronto. He is currently a Director's fellow in the Center for Nonlinear Studies at the Los Alamos National Laboratory in New Mexico. Chris uses theoretical approaches to understand the molecular mechanisms of life, with particular focus on proteins that are embedded in one of life's crucial peripheries: the cell membrane.