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Kirkwood–Buff Approach Rescues Overcollapse of a Disordered Protein in Canonical Protein Force Fields

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journal contribution
posted on 25.06.2015, 00:00 by Davide Mercadante, Sigrid Milles, Gustavo Fuertes, Dmitri I. Svergun, Edward A. Lemke, Frauke Gräter
Understanding the function of intrinsically disordered proteins is intimately related to our capacity to correctly sample their conformational dynamics. So far, a gap between experimentally and computationally derived ensembles exists, as simulations show overcompacted conformers. Increasing evidence suggests that the solvent plays a crucial role in shaping the ensembles of intrinsically disordered proteins and has led to several attempts to modify water parameters and thereby favor protein–water over protein–protein interactions. This study tackles the problem from a different perspective, which is the use of the Kirkwood–Buff theory of solutions to reproduce the correct conformational ensemble of intrinsically disordered proteins (IDPs). A protein force field recently developed on such a basis was found to be highly effective in reproducing ensembles for a fragment from the FG-rich nucleoporin 153, with dimensions matching experimental values obtained from small-angle X-ray scattering and single molecule FRET experiments. Kirkwood–Buff theory presents a complementary and fundamentally different approach to the recently developed four-site TIP4P-D water model, both of which can rescue the overcollapse observed in IDPs with canonical protein force fields. As such, our study provides a new route for tackling the deficiencies of current protein force fields in describing protein solvation.