Elucidating the origins of cooperativity and parallel pathways...
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Abstract:

Elucidating the origins of cooperativity and parallel pathways in protein folding with a
highly symmetrical repeat protein system

Speaker: Tural Aksel

Tural Aksel1, Ananya Majumdar2, Doug Barrick2
1Stanford University, 2Johns Hopkins University

The origins of cooperativity and the existence of parallel pathways in protein
folding are not well understood. Repeat proteins, owing to their symmetrical
topology, can provide answers to both questions. Using a highly symmetrical
repeat protein system, consensus ankyrin repeat proteins (CARPs), we were
able to determine the contributions of secondary structure folding, hydrophobic
desolvation and Coulombic interactions to folding stability at repeat level. Our
ndings show that hydrophobic desolvation is the major contributor to highly
favorable repeat-repeat interactions (interfacial energy), and -helix formation,
with unfavorable conformational entropy, makes the intrinsic repeat stability
(intrinsic energy) very low. Our salt dependent studies suggest that Coulom-
bic interactions between adjacent repeats are insignicant. The high stability
mismatch between favorable interfacial energy and the unfavorable intrinsic re-
peat energy makes CARP folding very cooperative. In addition, our observation
of the increase in CARP folding rate with number of repeats clearly indicate
that CARPs fold through parallel pathways. Our detailed dissection of folding
energetics and kinetics at repeat level is unique as it has not been done for
other systems. We believe our analysis and results will be the rst few steps to
experimental characterization of protein folding at residue level.