Oligoglycine is a backbone mimic for all proteins and is prevalent in the sequences of intrinsically disordered proteins. We have computed the absolute chemical potential of glycine oligomers at infinite dilution by simulation with the CHARMM36 and Amber ff12SB force fields. We performed a thermodynamic decomposition of the solvation free energy (ΔGsol) of Gly2–5 into enthalpic (ΔHsol) and entropic (ΔSsol) components as well as their van der Waals and electrostatic contributions. Gly2–5 was either constrained to a rigid/extended conformation or allowed to be completely flexible during simulations to assess the effects of flexibility on these thermodynamic quantities. For both rigid and flexible oligoglycine models, the decrease in ΔGsol with chain length is enthalpically driven with only weak entropic compensation. However, the apparent rates of decrease of ΔGsol, ΔHsol, ΔSsol, and their elec and vdw components differ for the rigid and flexible models. Thus, we find solvation entropy does not drive aggregation for this system and may not explain the collapse of long oligoglycines. Additionally, both force fields yield very similar thermodynamic scaling relationships with respect to chain length despite both force fields generating different conformational ensembles of various oligoglycine chains.
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