  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 description of IDPs/IDRs, but are largely in disagreement with
solution experiments for the disordered states. 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, and for seven globular proteins ranging in size
from 130-266 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.
