Multi-scaled explorations of binding-induced folding of intrinsically disordered protein inhibitor IA3 to its target enzyme

• Published in: PLoS computational biology 2011-04, Vol.7 (4), p.e1001118-e1001118
• Main Authors: Wang, Jin, Wang, Yong, Chu, Xiakun, Hagen, Stephen J, Han, Wei, Wang, Erkang
• Format: Article
• Language: English
• Subjects: Algorithms; Aspartic Acid Proteases - chemistry; Biophysics; Biophysics/Biomacromolecule-Ligand Interactions; Biophysics/Protein Folding; Biophysics/Theory and Simulation; Computational Biology - methods; Computational Biology/Molecular Dynamics; Computer Simulation; Experiments; Kinetics; Packaging; Pepsin A - chemistry; Physics/Interdisciplinary Physics; Protease inhibitors; Protein Binding; Protein Conformation; Protein Folding; Protein Structure, Tertiary; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - chemistry; Stochastic Processes; Studies; Surface Properties; Temperature; Thermodynamics; Yeast
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1001118

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.