Discriminating binding mechanisms of an intrinsically disordered protein via a multi-state coarse-grained model

Abstract

Many proteins undergo a conformational transition upon binding to their cognate binding partner, with intrinsically disordered proteins (IDPs) providing an extreme example in which a folding transition occurs. However, it is often not clear whether this occurs via an "induced fit" or "conformational selection" mechanism, or via some intermediate scenario. In the first case, transient encounters with the binding partner favour transitions to the bound structure before the two proteins dissociate, while in the second the bound structure must be selected from a subset of unbound structures which are in the correct state for binding, because transient encounters of the incorrect conformation with the binding partner are most likely to result in dissociation. A particularly interesting situation involves those intrinsically disordered proteins which can bind to different binding partners in different conformations. We have devised a multi-state coarse-grained simulation model which is able to capture the binding of IDPs in alternate conformations, and by applying it to the binding of nuclear coactivator binding domain (NCBD) to either ACTR or IRF-3 we are able to determine the binding mechanism. By all measures, the binding of NCBD to either binding partner appears to occur via an induced fit mechanism. Nonetheless, we also show how a scenario closer to conformational selection could arise by choosing an alternative non-binding structure for NCBD. © 2014 AIP Publishing LLC.

Aggregation and network formation in self-assembly of protein (H3.1) by a coarse-grained Monte Carlo simulation

“…Zuckerman 30 has used a united residue model with a structure-based potential, i.e., the Go model 25 with double native structures to probe the conformational phase space of Calmodulin. Knott and Best 31 have used a multi-state coarse-grained description, somewhat similar to the double Go model, to analyze the binding mechanism of an intrinsically disordered protein. These studies [27][28][29][30][31] involve protein structures in devising the models and are very useful in examining the structural evolutions spanning over a large time scale.…”

“…Knott and Best 31 have used a multi-state coarse-grained description, somewhat similar to the double Go model, to analyze the binding mechanism of an intrinsically disordered protein. These studies [27][28][29][30][31] involve protein structures in devising the models and are very useful in examining the structural evolutions spanning over a large time scale. It is not common to see such a detailed analysis of fractality 27 and structure factors 28, 29 that span multiple scales in protein modeling, particularly in crowded systems.…”

Expanding the Range of Protein Function at the Far End of the Order-Structure Continuum

“…These simulations argue that the IRF-3 bound conformation is only rarely accessible from the unbound state, indicating that the presence of that binding partner may be necessary for NCBD to sample that state (58). A separate molecular dynamics simulation study of NCBD binding to its interaction domain on the human activator for thyroid hormone and retinoid receptors protein (ACTR) or IRF-3 indicated that NCBD samples its bound conformation for each of these partners much more readily in the presence of that partner than in its absence (59).…”

“…4). Molecular dynamics simulations of the unbound state have shown that NCBD samples a wide variety of conformations characterized by different orientations and lengths of its helices (58,59). Long time-scale simulations indicated that NCBD samples conformations similar to each known bound structure at low rates.…”

Quarterly intrinsic disorder digest (April–May–June, 2014)

“…They found that NCBD binding to either partner occurs via an induced fit mechanism. 21 Gianni et al describe a kinetic method which distinguishes induced fit from conformational selection and relies on an observation of the rate constant for binding while varying the protein and ligand concentrations in separate experiments. 22 Using statistical mechanics, calorimetry, and NMR spectroscopy, Krieger et al showed conformational selection in the binding of a fragment of the IDP Gab2 to the growth factor receptor-bound protein 2 (Grb2).…”