*Article* **Configurational Entropy of Folded Proteins and Its Importance for Intrinsically Disordered Proteins**

**Meili Liu 1,2,3, Akshaya K. Das 2,3, James Lincoff 2,4, Sukanya Sasmal 2,4 , Sara Y. Cheng 2,3, Robert M. Vernon 5, Julie D. Forman-Kay 5,6 and Teresa Head-Gordon 2,3,4,7,\***


**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.

**Keywords:** configurational entropy; force fields; intrinsically disordered proteins
