Intrinsically disordered proteins are attractive therapeutic targets owing to their prevalence in several diseases. Yet their lack of well-defined structure renders ligand discovery a challenging task. An intriguing example is provided by the oncoprotein c-Myc, a transcription factor that is over expressed in a broad range of cancers. Transcriptional activity of c-Myc is dependent on heterodimerization with partner protein Max. This protein-protein interaction is disrupted by the small molecule 10058-F4 (1), that binds to monomeric and disordered c-Myc. To rationalize the mechanism of inhibition, structural ensembles for the segment of the c-Myc domain that binds to 1 were computed in the absence and presence of the ligand using classical force fields and explicit solvent metadynamics molecular simulations. The accuracy of the computed structural ensembles was assessed by comparison of predicted and measured NMR chemical shifts. The small molecule 1 was found to perturb the composition of the apo equilibrium ensemble and to bind weakly to multiple distinct c-Myc conformations. Comparison of the apo and holo equilibrium ensembles reveals that the c-Myc conformations binding 1 are already partially formed in the apo ensemble, suggesting that 1 binds to c-Myc through an extended conformational selection mechanism. The present results have important implications for rational ligand design efforts targeting intrinsically disordered proteins.
An efficient molecular simulation methodology has been developed for the evaluation of the druggability (ligandability) of a protein. Previously proposed techniques were designed to assess the druggability of crystallographic structures and cannot be tightly coupled to molecular dynamics (MD) simulations. By contrast, the present approach, JEDI (Just Exploring Druggability at protein Interfaces), features a druggability potential made of a combination of empirical descriptors that can be collected "on-the-fly" during MD simulations. Extensive validation studies indicate that JEDI analyses discriminate druggable and nondruggable protein binding site conformations with accuracy similar to alternative methodologies, and at a fraction of the computational cost. Since the JEDI function is continuous and differentiable, the druggability potential can be used as collective variable to rapidly detect cryptic druggable binding sites in proteins with a variety of MD free energy methods. Protocols for applications to flexible docking problems are outlined.
IDPs (intrinsically disordered proteins) play crucial roles in many important cellular processes such as signalling or transcription and are attractive therapeutic targets for several diseases. The considerable structural flexibility of IDPs poses a challenge for rational drug discovery approaches. Consequently, structure-based drug design efforts to date have mostly focused on inhibiting interactions of IDPs with other proteins whose structure can be solved by conventional biophysical methods. Yet, in recent years, several examples of small molecules that bind to monomeric IDPs in their disordered states have been reported, suggesting that this approach may offer new opportunities for therapeutic interventions. Further developments of this strategy will greatly benefit from an improved understanding of molecular recognition mechanisms between small molecules and IDPs. The present article summarizes findings from experimental and computational studies of the mechanisms of interaction between small molecules and three IDPs in their disordered states: c-Myc, Aβ (amyloid β-peptide) and α-synuclein.
with a conformational selection mechanism for binding. These results are also consistent with PMFs for NMDA but not AMPA receptor LBDs. Additionally, the open-cleft conformation is more accessible to the GluK2 apo state than the glutamate-bound state, consistent with previous results for both NMDA and AMPA receptors. Small-angle X-ray scattering profiles for the apo-and glutamate-bound states calculated from a Boltzmann-weighted ensemble of conformations are compared with experimental SAXS profiles. Finally, structural and biochemical properties of GluK2 in its apo state are probed using proteolytic protection assays, circular dichroism, and multi-angle light scattering.
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