ADD Force Field for Sugars and Polyols: Predicting the Additivity of Protein-Osmolyte Interaction

Abstract

The protein-osmolyte interaction has been shown experimentally to follow an additive construct, where the individual osmolyte-backbone and osmolyte-side-chain interactions contribute to the overall conformational stability of proteins. Here, we computationally reconstruct this additive relation using molecular dynamics simulations, focusing on sugars and polyols, including sucrose and sorbitol, as model osmolytes. A new set of parameters (ADD) is developed for this purpose, using the individual Kirkwood-Buff integrals for sugar-backbone and sugar-side-chain interactions as target experimental data. We show that the ADD parameters can reproduce the additivity of protein-sugar interactions and correctly predict sucrose and sorbitol self-association and their interaction with water. The accurate description of the separate osmolyte-backbone and osmolyte-side-chain contributions also automatically translates into a good prediction of preferential exclusion from the surface of ribonuclease A and α-chymotrypsinogen A. The description of sugar polarity is improved compared to previous force fields, resulting in closer agreement with the experimental data and better compatibility with charged groups, such as the guanidinium moiety. The ADD parameters are developed in combination with the CHARMM36m force field for proteins, but good compatibility is also observed with the AMBER 99SB-ILDN and the OPLS-AA force fields. Overall, exploiting the additivity of protein-osmolyte interactions is a promising approach for the development of new force fields.

Figure 1

KB integrals (γ = G₂₃ – G₁₂) for the N-acetyl glycinamide series NAG_xA, as a function of the number of internal glycine units x. The results shown in panel (a) were obtained for 1 M sucrose and using the KBP force field. Panel (b) displays results for the ADD force field. Here, the solid line with red squares is for 1 M sucrose, while the dashed one with red circles is for 1 M sorbitol.

Figure 2

KB integrals γ^sc and γ^bb for the different amino acids side chains and the backbone and for (a) 1 M sucrose or (b) 1 M sorbitol as model osmolytes. Red, black, and dashed bars correspond to the KBP, the ADD, and the experimental data,^, respectively. In both panels, the amino acids are divided into groups, depending on their side-chain properties (nonpolar, polar, aromatic, and positively and negatively charged, moving from left to right), and ordered according to their molecular weight (increasing from left to right) in each group. Zwitterionic amino acids were used in the simulations.

Figure 3

(a) RMSE between experimental and simulated values of γ^sc for Ala and Asn, as a function of the O and H charges. The Lennard-Jones parameters were the same as for the KBP force field. (b) RMSE between experimental and simulated values of KB integrals G₃₃ and G₁₃ as a function of the Lennard-Jones parameters ε for water interaction. The O and H partial charges were set to −0.65 and 0.33, respectively. The data shown in both panels are for 1 M sucrose as the model osmolyte.

Figure 4

χ parameter for the different amino acids in (a) 1 M sucrose or (b) 1 M sorbitol, as obtained with the KBP (red bars) or ADD (black bars) force fields.