multi-scaled explorations of binding-induced folding of intrinsically disordered protein inhibitor ia3 to its target enzyme多尺度探索内在无序蛋白质的折叠binding-induced抑制剂ia3目标酶.pdfVIP

Multi-Scaled Explorations of Binding-Induced Folding of Intrinsically Disordered Protein Inhibitor IA3 to its Target Enzyme 1,2,3 1 2 4 2 1 Jin Wang *, Yong Wang , Xiakun Chu , Stephen J. Hagen , Wei Han , Erkang Wang * 1 State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, People’s Republic of China, 2 College of Physics, Jilin University, Changchun, Jilin, People’s Republic of China, 3 Department of Chemistry, Physics and Applied Mathematics, State University of New York at Stony Brook, Stony Brook, New York, United States of America, 4 Department of Physics, University of Florida, Gainesville, Florida, United States of America Abstract Biomolecular function is realized by recognition, and increasing evidence shows that recognition is determined not only by structure but also by flexibility and dynamics. We explored a biomolecular recognition process that involves a major conformational change – protein folding. In particular, we explore the binding-induced folding of IA3, an intrinsically disordered protein that blocks the active site cleft of the yeast aspartic proteinase saccharopepsin (YPrA) by folding its own N-terminal residues into an amphipathic alpha helix. We developed a multi-scaled approach that explores the underlying mechanism by combining structure-based molecular dynamics simulations at the residue level with a stochastic path method at the atomic level. Both the free energy profile and the associated kinetic paths reveal a common scheme whereby IA3 binds to its target enzyme prior to folding itself into a helix. This theoretical result is consistent with recent time-resolved experiments. Furthermore, exploratio