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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.

SUBMITTER: Knott M

PROVIDER: S-EPMC4032430 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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

Knott Michael M Best Robert B RB

The Journal of chemical physics 20140501 17

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, ...[more]

PMID: 24811666

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Project description:Efficient coarse-grained (CG) models can be coupled with atomistic force fields to accelerate the sampling of atomistic energy landscapes in the multi-scale enhanced sampling (MSES) framework. This approach may be particularly suitable for generating atomistic conformational ensembles of intrinsically disordered proteins (IDPs). While MSES is relatively robust to inherent CG artifacts, achieving optimal sampling efficiency requires CG modeling to generate the local and long-range fluctuations that are largely consistent with those at the atomistic level. Here, we describe a new hybrid resolution CG model (HyRes) for MSES simulations of disordered protein states, which is specifically designed to provide semi-quantitative secondary structure propensities together with a qualitative description of long-range nonspecific interactions. The HyRes model contains an atomistic description of the backbone with intermediate resolution side chains. The secondary structure propensities are tuned by adjusting the backbone hydrogen-bonding strength and the ?/? torsion profile. The sizes and covalent geometries of the side chains are parameterized to reproduce distributions derived from atomistic simulations. Lennard-Jones parameters for sidechain beads are assigned to reproduce statistical potentials derived from the protein structural database, and then globally parameterized with nonspecific electrostatic interactions to reproduce the free energy profiles of pair wise interactions and the key conformational properties of model peptides. Application of HyRes to MSES simulations of small IDPs suggests that it is capable of driving faster structural transitions at the atomistic level and increasing the convergence rate compared to the C?-only G?-like models previously utilized. With further optimization, we believe that the new CG model could greatly improve the efficiency of MSES simulations of the larger and more complex IDPs frequently involved in cellular signalling and regulation.

Dataset Information

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

Publications

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

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