Enthalpy-Entropy Compensation and Isoequilbria Implicate Solvation as the Driving Force for Amino Acid Conformational Propensity

Abstract

The existence of residual structure in intrinsically disordered proteins (IDPs) raise questions regarding how disorder/order preferences are encoded in the peptide sequence. In addition to formation of local secondary structure, individual amino acids sample unique and restricted conformational space, contrary to the predictions of the random coil model. To understand the thermodynamic driving forces underlying these newly discovered amino acid conformational biases, we have examined the thermodynamics governing these intrinsic conformational propensities in a series of host-guest experiments on model “GxG” peptides in aqueous solution. Global two-state pPII/β thermodynamic analysis of UVCD and HNMR data revealed the existence of a nearly exact enthalpy-entropy compensation for the pPII-β equilibrium for all residues. The obtained ΔH/ΔS values exhibit a nearly perfect linear relationship reflecting compensation temperature of 295K ± 2 K. We identified iso-equilibria for two subsets of the investigated peptides, indicating that pPII and β propensities of most residues become similar at physiological temperature, in spite of rather large differences between respective enthalpic and entropic differences. Interestingly, alanine, aspartic acid, and threonine, which have largely biased intrinsic conformational propensities, are the only amino acid residues that do not share iso-equilibria. We assign the isoequilibria to a common enthalpy-entropy compensation which occurs in the hydration shell of side chains with considerable hydrophobic content. Aspartic acid and threonine deviate from this behavior owing to their capability to form hydrogen bonds with the backbone even in extended structures, whereas the solvation energy of alanine is dominated by backbone - solvent interactions.