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.
Highlights
Carbohydrates, including sugars and polyols, are a common class of osmolytes and play a crucial role in biological systems
We show that the additivity of protein−osmolyte interaction can be reproduced using ADD sugars, and this automatically translates into a prediction of preferential exclusion from ribonuclease A (RNase A) and α-chymotrypsinogen A (α-Cgn A), which is in good agreement with the experimental data
There is no change in the σ parameter for the alcohol atoms in the KBP force field compared to the original CHARMM36
Summary
Carbohydrates, including sugars and polyols, are a common class of osmolytes and play a crucial role in biological systems. Several force fields were proposed in the literature for carbohydrates,[10−14] and Cloutier et al.[15] have recently developed new parameters for these molecules (which they named KBPs), by modifying the original CHARMM36 force field.[16−18] They used the Kirkwood−Buff (KB) integrals[19−22] as target experimental data and showed that the new force field could accurately predict both self-association and exclusion of carbohydrates from the protein surface This represents a crucial step forward in our understanding of protein−sugar interactions, especially considering that previous parameters often overestimated sugar self-interaction[23] and resulted in sugar molecules that were preferentially interacting with the protein.[18]
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