title: Multi-scaled explorations of binding-induced folding of intrinsically disordered protein inhibitor IA3 to its target enzyme.
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, exploration of the detailed trajectories reveals the important roles of non-native interactions in the initial binding that occurs prior to IA3 folding. In contrast to the common view that non-native interactions contribute only to the roughness of landscapes and impede binding, the non-native interactions here facilitate binding by reducing significantly the entropic search space in the landscape. The information gained from multi-scaled simulations of the folding of this intrinsically disordered protein in the presence of its binding target may prove useful in the design of novel inhibitors of aspartic proteinases.
authors.affiliation: State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, People's Republic of China. jin.wang.1@stonybrook.edu
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiakun
authors.initials: X
authors.lastname: Chu
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Hagen
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.forename: Erkang
authors.initials: E
authors.lastname: Wang
mesh_terms: D000465:Algorithms; D057055:Aspartic Acid Proteases / Q000737:chemistry; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D007700:Kinetics; D010434:Pepsin A / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry*; D013269:Stochastic Processes; D013499:Surface Properties; D013696:Temperature; D013816:Thermodynamics
chemical_list: C018134:PAI3 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D057055:Aspartic Acid Proteases; D010434:Pepsin A