Residual Structure Accelerates Binding of Intrinsically Disordered ACTR by Promoting Efficient Folding upon Encounter

• Published in: Journal of molecular biology Vol. 431; no. 2; pp. 422 - 432
• Main Authors: Liu, Xiaorong, Chen, Jianlin, Chen, Jianhan
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 18.01.2019
• Subjects: binding kinetics; conformational selection; coupled binding and folding; CREB-Binding Protein - metabolism; Humans; Intrinsically Disordered Proteins - metabolism; Kinetics; molecular dynamics; Molecular Dynamics Simulation; Nuclear Receptor Coactivator 3 - metabolism; Protein Binding - physiology; Protein Folding; Thermodynamics; topology-based modeling; NCBD; topology-based modeling; IDP; REX; binding kinetics; MD; MFPT; molecular dynamics; coupled binding and folding; ACTR; conformational selection
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2018.12.001

Intrinsically disordered proteins (IDPs) often fold into stable structures upon specific binding. The roles of residual structure of unbound IDPs in coupling binding and folding have been under much debate. While many studies emphasize the importance of conformational flexibility for IDP recognition, it was recently demonstrated that stabilization the N-terminal helix of intrinsically disordered ACTR accelerated its binding to another IDP, NCBD of the CREB-binding protein. To understand how enhancing ACTR helicity accelerates binding, we derived a series of topology-based coarse-grained models that mimicked various ACTR mutants with increasing helical contents and reproduced their NCBD binding affinities. Molecular dynamics simulations were then performed to sample hundreds of reversible coupled binding and folding transitions. The results show that increasing ACTR helicity does not alter the baseline mechanism of synergistic folding, which continues to follow “extended conformational selection” with multiple stages of selection and induced folding. Importantly, these coarse-grained models, while only calibrated based on binding thermodynamics, recapitulate the observed kinetic acceleration with increasing ACTR helicity. However, the residual helices do not enhance the association kinetics via more efficient seeding of productive collisions. Instead, they allow the nonspecific collision complexes to evolve more efficiently into the final bound and folded state, which is the primary source of accelerated association kinetics. Meanwhile, reduced dissociation kinetics with increasing ACTR helicity can be directly attributed to smaller entropic cost of forming the bound state. Altogether, this study provides important mechanistic insights into how residual structure may modulate thermodynamics and kinetics of IDP interactions. [Display omitted] •Mechanistic roles of residual structure in IDP binding remain intensely debated.•Topology-based modeling recapitulates increasing ACTR helicity enhances binding rate.•Residual helices mainly promote more efficient folding following binding.•Efficient folding upon binding is critical for achieving fast IDP association kinetics