College of Liberal Arts & Sciences

Exploring the function of a pH-mediated protein chaperone using models on multiple scales

Tuesday, February 3, 2015

February 3, Tue 2015
1:30 pm, Haworth Hall, Room 1005

Dr. Charles Brooks

Warner-Lambert/Parke-Davis Professor of Chemistry and Biophysics, Department of Chemistry and Biophysics, University of Michigan

Exploring the function of a pH-mediated protein chaperone using models on multiple scales

The small protein HdeA is part of the pH-stress response of enteric bacteria like E. coli to protect its periplasmic proteins as the bug transits the harsh low pH 2 environment of the human stomach. Using our novel constant pH molecular dynamics approach, we will discuss how we uncovered the key pH sensing elements of this system and reengineered a pH-independent constitutively active chaperone in which the inactive dimer is destabilized and transformed to a dominant conditionally disordered monomeric chaperone. We will further describe the development of a multi-scale approach to enable the exploration of the pH-dependent equilibrium between ordered, and chaperone inactive, dimer state and the largely disordered monomeric state that is active as a chaperone “holdase” by combining coarse-grained molecular models with detailed all atom models. Finally, we will describe progress toward describing the nature of the chaperone active ensemble of this protein and its interactions with substrate proteins.p>



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