Preferential interactions between small solutes and the protein backbone: A computational analysis

To improve our understanding of the effects of small solutes on protein stability, we conducted atomistic simulations to quantitatively characterize the interactions between two broadly used small solutes, urea and glycine betaine (GB), and a triglycine peptide, which is a good model for a protein backbone. Multiple solute concentrations were analyzed, and each solute−peptide−water ternary system was studied with ∼200−300 ns of molecular dynamics simulations with the CHARMM force field. The comparison between calculated preferential interaction coefficients (Γ23) and experimentally measured values suggests that semiquantitative agreement with experiments can be obtained if care is exercised to balance interactions among the solute, protein, and water. On the other hand, qualitatively incorrect (i.e., wrong sign in Γ23) results can be obtained if a solute model is constructed by directly taking parameters for chemically similar groups from an existing force field. Such sensitivity suggests that small solut...