New estimate of beta-sheet folding cooperativity based on molecular dynamics simulations of a three-stranded beta-sheet

COMP 192

Daniel R. Roe, droe@ic.sunysb.edu, Department of Chemistry, Stony Brook University, Stony Brook University, Chemistry Dept, Stony Brook, NY 11794, Viktor Hornak, viktor.hornak@sunysb.edu, Center for Structural Biology, Stony Brook University, Stony Brook, NY 11794, and Carlos Simmerling, carlos@csb.sunysb.edu, Department of Chemistry, State University of New York at Stony Brook, stony brook, NY 11790.
The thermodynamic behavior of a three-stranded anti-parallel beta-sheet was studied via two replica exchange molecular dynamics simulations starting from different unfolded structures. Both simulations find a fully folded sheet consistent with experimental results. Matching previous predictions of non-two-state folding, a four-state free-energy landscape is observed. Folding cooperativity perpendicular to strand direction was observed and quantified. Cooperativity was measured by observing how the free energy profile for forming a hairpin is affected by the presence or absence of the other hairpin. A lower limit of cooperativity is observed in experiments as the presence or absence of the other hairpin is uncertain. The atomic level detail of these simulations allows hairpin states to be known at all times, allowing a more direct measure of cooperativity. The cooperativity is observed to be 2 kcal/mol larger than the previously obtained lower limit.