Coupled folding–binding versus docking: A lattice model study

Abstract

Using a simple hydrophobic/polar protein model, we perform a Monte Carlo study of the thermodynamics and kinetics of binding to a target structure for two closely related sequences, one of which has a unique folded state while the other is unstructured. We obtain significant differences in their binding behavior. The stable sequence has rigid docking as its preferred binding mode, while the unstructured chain tends to first attach to the target and then fold. The free-energy profiles associated with these two binding modes are compared. * Electronic address: nitingpt@iitk.ac.in † Electronic address: anders@thep.lu.se

Kinetic Advantage of Intrinsically Disordered Proteins in Coupled Folding–Binding Process: A Critical Assessment of the “Fly-Casting” Mechanism

“…However, the inclusion of diffusion will remove this consistency. Although Q b is widely used in protein binding problems, [35][36][37]64 our results indicate that this parameter is not a good reaction coordinate for describing the binding process. Q b cannot discriminate different states within the unbound states and the nonnative encounter complex, whereas it can monitor the evolution process from the encounter state to the bound state.…”

“…Ordered proteins dock to their targets through induced-fit or conformational selection, 37,48 whereas IDPs bind to their targets coupled with folding 21 (the binding of IDPs may also possess some components of conformational selection if they populate "preformed elements"; 49,50 however, the preformed structures will be stabilized and folded further upon binding). 51 Changing α values in our scheme regulates the system between coupled folding-binding and docking (Fig.…”

“…A simulation with the HP lattice model has also shown that both mechanisms can be observed in the binding process regardless of whether the protein is ordered or disordered, whereas the preference of binding mechanisms is different. 37 For weak intrachain interactions (e.g., α = 0.1), free pKID has only 38% of the native contacts and can be considered disordered. Initial weak binding with KIX domain (Q b ≤ 0.2) does not cause marked folding of the pKID domain.…”

A Survey of Flexible Protein Binding Mechanisms and their Transition States Using Native Topology Based Energy Landscapes

“…7 The degree of plasticity involved in protein binding has been recently investigated by molecular dynamics simulations. [8][9][10] Protein flexibility has also been invoked in the model of "conformational selection", [11][12][13][14] which suggests that binding entails choice of the correct conformer for binding out of a rapidly interconverting ensemble. Selection of specific protein conformers and the presence of conformational isomerism prior to association has been shown by kinetic and equilibrium studies, 15,16 as well as by NMR.…”

The significance of molecular mechanics property to protein evolution

“…With revealment of features of hydrophobic interactions, scientists have achieved many progresses in characterising protein's properties, such as folding mechanism (Li et al, 1996(Li et al, , 1997, marginal stability (Taverna and Goldstein, 2002;Bloom et al, 2004), kinetics of function (Gupta and Irbäck, 2004), and etc. Owing to its importance to protein molecule, hydrophobic interaction is an ideal aspect in evaluating the significance and contribution of different physical quantities to protein homology.…”