While the ability of intrinsically disordered regions (IDRs) in proteins to regulate and mediate protein interactions is well accepted, their thermodynamic role in general and the entropic contribution to the overall binding energetics in particular remain elusive. Towards developing a predictive protein binding model that explicitly accounts for IDR flexibility and entropic contributions, we used a combination of molecular dynamics (MD) simulations and computational biophysics to investigate the structural and thermodynamic properties of polyglycine, a model, disordered polypeptide. Initially, using a variety of structural metrics (e.g. end-to-end distance, radius of gyration, dihedral angles), we characterized the distributions of Gly3 and Gly10 conformers from all-atom MD simulations with the CHARMM27 (C27), CHARMM36 (C36), and Amber ff12SB force fields. Most notably, we showed how the solution properties of glycine oligomers depend on force field and that C36 samples more extended structures with individual glycine residues largely sampling dihedral angles in the polyproline-II region, consistent with experimental results. Next, using free energy methods with C36 and ff12SB, we examined how solvation free energy (ΔG) and entropy (ΔS) and their Van der Waals (ΔGVDW/ΔSVDW) and electrostatic (ΔGELEC/ΔSELEC) components scale with the number of residues in completely rigid and flexible polyglycines, separately. We found that despite the fact that ΔGVDW,ΔGELEC,ΔSVDW,and ΔSELEC scale differently with the number of glycine residues for C36 and ff12SB, the total solvation entropy, ΔS, between the force fields is remarkably similar for both rigid and flexible polyglycine. Additionally, we showed that conformational flexibility favorably contributes to ΔS and the difference between ΔS for rigid and flexible polyglycines continues to increase with number of residues. Finally, we estimated conformational entropy directly using histogramming methods and the quasi-harmonic approximation for polyglycines differing in length and as a function of physical constraints.

How structural and thermodynamic properties scale with the length of a model, disordered polypeptide

251st National Meeting (2016)

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