Abstract
Many pairwise additive force fields are in active use for intrinsically disordered proteins (IDPs) and regions (IDRs), some of which modify energetic terms to improve the description of IDPs/IDRs but are largely in disagreement with solution experiments for the disordered states. This work considers a new direction—the connection to configurational entropy—and how it might change the nature of our understanding of protein force field development to equally well encompass globular proteins, IDRs/IDPs, and disorder-to-order transitions. We have evaluated representative pairwise and many-body protein and water force fields against experimental data on representative IDPs and IDRs, a peptide that undergoes a disorder-to-order transition, for seven globular proteins ranging in size from 130 to 266 amino acids. We find that force fields with the largest statistical fluctuations consistent with the radius of gyration and universal Lindemann values for folded states simultaneously better describe IDPs and IDRs and disorder-to-order transitions. Hence, the crux of what a force field should exhibit to well describe IDRs/IDPs is not just the balance between protein and water energetics but the balance between energetic effects and configurational entropy of folded states of globular proteins.
Highlights
Disordered peptides (IDPs) are a class of proteins that are defined as dynamic structural ensembles rather than a dominant equilibrium structure in solution [1]
We have presented a comparison of a range of pairwise additive force fields and the many-body force field AMOEBA to test their ability to simultaneously describe the stable folded states of seven globular proteins, proteins with regions of disorder illustrated with the TSR4 domain, the Histatin 5 (Hst 5) Intrinsically disordered peptides (IDPs), and the partial disorder-to-order transition as the temperature is lowered for the (AAQAA)3 peptide
We find that the fixed-charge force fields yield small root mean square deviation (RMSD) differences from the PDB structures of the folded globular proteins, whereas the polarizable model has larger RMSD values that are within the expectations from solution experiments [48,49,50] on folded states
Summary
Disordered peptides (IDPs) are a class of proteins that are defined as dynamic structural ensembles rather than a dominant equilibrium structure in solution [1]. An example is the CHARMM36m protein model of Huang et al that purports to better describe both IDPs and folded proteins using the same set of refined peptide backbone parameters and salt–bridge interactions and an increased Lennard–Jones (LJ) well depth to strengthen protein–water dispersion interactions [30] These modifications led to a reduction in the percentage of predicted left-handed a-helices, as well as a better agreement with NMR scalar couplings and SAXS curves for folded proteins, Huang et al observed that no universal interaction strength parameter in the Lennard–Jones function could generate structural ensembles with good agreement with the experimental radius of gyration measurements for all IDP systems [30]. This work better places theory as an equal partner to experiment in new areas of IDP studies such as liquid–liquid phase separation that are current and active areas of theory/experimental collaboration
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