Abstract: Alternative inactive state of human β_2-adrenergic receptor (β_2-AR) originally exposed in Molecular Dynamics simulations was investigated using various analysis tools to evaluate causality between correlated residue-pair fluctuations and suggest allosteric communication pathways. Major conformational shift observed in the third intracellular loop (ICL3) displayed a novel inactive state, featuring an inaccessible G-protein binding site blocked by ICL3 and an expanded orthosteric ligand-binding site. Residue-based mean-square fluctuation and stiffness calculations revealed significant mobility decrease in ICL3, which induced mobility increase in remaining loop regions. This indicates conformational entropy loss in one mobile region being compensated by residual intermolecular motions in other mobile regions. Moreover, extent of significantly correlated motions decreased and correlations once existed between transmembrane helices shifted towards regions with increased mobility. Conditional time-delayed cross-correlation analysis identified distinct driver-follower relationship profiles. Prior to its packing, freely moving ICL3 was markedly driven by transmembrane helix-8 whereas once packed, ICL3 controlled future fluctuations of nearby helices. Moreover, two transmembrane helices, (H5-H6), started to control future fluctuations of a remote site, the extracellular loop, ECL2. This clearly suggests that allosteric coupling between extra- and intracellular parts intensified, in agreement with receptor’s well recognized feature which is inverse proportionality between activity and degree of coupling.

Speaker Biography: Dr. Demet Akten Akdoğan completed her BS and MS degrees in Chemical Engineering at Boğaziçi University, Istanbul, Turkey, in 1994 and 1996, respectively. She later joined Prof. Wayne L. Mattice's research group as a PhD student and received her degree in Polymer Science at the University of Akron in 2001. As a postdoctoral scholar, she worked with Prof. Sholl at Carnegie Mellon University and later with Prof. Schultz at the Scripps Research Institute between 2001-2004. Her research interests include the study of allostery and intrinsic dynamics of proteins using their fully atomistic models and computational tools such as Molecular Dynamics simulation. In addition, she is interested in developing novel knowledge-based algorithms for predicting protein-protein interfaces. She is a faculty member at the Bioinformatics and Genetics Department at Kadir Has University, since 2008.

Webpage: http://sites.khas.edu.tr/bioinformatics/research/e-demet-akdogan/

https://scholar.google.com/citations?user=5uo-HG4AAAAJ&hl=en