Intrinsically disordered proteins (IDPs) are proteins without fixed structures. However, they exhibit important biological functions such as cell signaling, regulation, and recognition [Uversky, (2014)]. Hence, they complement the functions of structured proteins outside the realm of the structure-function paradigm. The lack of a well-defined structure challenges the ability of traditional structural biology methodologies to identify the working mechanisms of IDPs. In-silico computer simulations, and theoretical models provide powerful tools to investigate the function and behavior of IDPs in biomolecular environments and shed light into the world of IDPs, which still holds many unknowns. However, simulations are limited by the accuracy of empirical force field models used to describe the underlying potential energy surface, which will be investigated here. The thermodynamics of protein folding and protein-protein interactions are strongly modulated by interactions between proteins and their surrounding solvent medium. The impact of solvation on biomolecular processes can be understood in terms of changes in the solvation free energy, DGsolv. Our lab developed the 3D-2PT [Persson et al., (2017)] method to obtain spatially resolved information on DGsolv and its enthalpic/entropic contributions from equilibrium molecular dynamics simulations in explicit water, which allows us to understand the role of solvation in biomolecular processes with unprecedented detail. Here, we apply the 3D-2PT method to the K-18 domain of the IDP Tau to study its solvation in simulations based on distinct empirical force field models. Previous work showed that conformational ensembles of IDPs in simulations with standard empirical force fields deviate significantly from experimental observations [Best et al., (2014)]. Varying implementations of scaled protein-water interactions, which effectively modify the solvation free energy, have been proposed and resulted in substantially improved agreement between simulations and experiment [Huang et al., (2017)]. However, our spatially resolved analysis of solvation free energy contributions demonstrates distinct thermodynamic effects of existing strategies to scale protein-water interactions. Consequently, simulations based on scaled protein-water interactions do not necessarily produce the right answers for the right reasons.

Solvation thermodynamics of intrinsically disordered proteins (IDP)

2019 Fall National Meeting

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