Comparison of Methodologies\nfor Absolute Binding Free\nEnergy Calculations of Ligands to Intrinsically Disordered Proteins

Modulating the function of Intrinsically Disordered Proteins\n(IDPs)\nwith small molecules is of considerable importance given the crucial\nroles of IDPs in the pathophysiology of numerous diseases. Reported\nbinding affinities for ligands to diverse IDPs vary broadly, and little\nis known about the detailed molecular mechanisms that underpin ligand\nefficacy. Molecular simulations of IDP ligand binding mechanisms can\nhelp us understand the mode of action of small molecule inhibitors\nof IDP function, but it is still unclear how binding energies can\nbe modeled rigorously for such a flexible class of proteins. Here,\nwe compare alchemical absolute binding free energy calculations (ABFE)\nand Markov-State Modeling (MSM) protocols to model the binding of\nthe small molecule 10058-F4 to a disordered peptide extracted from\na segment of the oncoprotein c-Myc. The ABFE results produce binding\nenergy estimates that are sensitive to the choice of reference structure.\nIn contrast, the MSM results produce more reproducible binding energy\nestimates consistent with weak mM binding affinities and transient\nintermolecular contacts reported in the literature.