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Configurational Entropy of Folded Proteins and Its Importance for Intrinsically Disordered Proteins - PubMed

  • ️Fri Jan 01 2021

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

Meili Liu et al. Int J Mol Sci. 2021.

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.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1

Seven folded proteins (PDB IDs: 1b6b [37], 1arb [38] 1bsg [39], 1rii [40], 2xr6 [41], 4r3f [42], and 4xq4 [43]) and one protein with intrinsically disordered regions (1vex [44]) simulated with polarizable and nonpolarizable force fields.

Figure 2
Figure 2

Measures of protein stability when simulated with polarizable and nonpolarizable force fields. (a) Root mean square deviation (RMSD) for 1 μs MD simulations for AmPro13/AmW03, C36m/TIP3P, C36m/TIP3Pm, ff99SB/TIP3P, and ff99SB/TIP4P-Ew. The black line is the value of the D0, sim metric and the red line the metric and the red line the D0, dis metric. (b) <Rg> for all force fields and comparison to the Rg of the PDB structure (black) or polymer scaling laws (Supplementary Table S2) as a measure of solution (red). Proteins characterized are 1arb [38] 1b6b [37], 1bsg [39], 1rii [40] 4xq4 [43], 4r3f [42] and 2xr6 [41]

Figure 3
Figure 3

Average root mean square fluctuation for each residue in the simulated trajectories averaged over the last 100 ns. For 1arb [38] 1b6b [37], 1bsg [39], 1rii [40] 4xq4 [43], 4r3f [42] and 2xr6 [41].

Figure 4
Figure 4

Structural properties for Hst 5 using polarizable and nonpolarizable force fields. (a) Probability density estimates of the radius of gyration and (b) average percentages of different secondary structures features for the disordered Hst 5 peptide.

Figure 5
Figure 5

Structural properties for (AAQAA)3 using polarizable and nonpolarizable force fields. Comparison of estimated helical propensities from NMR (pink), average α−helix from the simulation assuming 3 sequential residues (black), and pairwise average over any presence of α−helix, π−helix, and 310 helix for (a) C36m/TIP3Pm (blue) and (b) AmPro13/AmW03 (gray) at 300 K. Comparison of changes in helix propensity with temperature at 300 and 360 K for (c) C36m/TIP3Pm and (d) AmPro13/AmW03.

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