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Coarse-grained (CG) models have been successful in simulating the chemical properties of lipid bilayers, but accurate treatment of membrane proteins and lipid-protein molecular interactions remains a challenge. The CgProt force field, original developed with the multiscale coarse graining method, is assessed by comparing the potentials of mean force for sidechain insertion in a DOPC bilayer to results reported for atomistic molecular dynamics simulations. Reassignment of select CG sidechain sites from the apolar to polar site type was found to improve the attractive interfacial behavior of tyrosine, phenylalanine and asparagine as well as charged lysine and arginine residues. The solvation energy at membrane depths of 0, 1.3 and 1.7 nm correlates with experimental partition coefficients in aqueous mixtures of cyclohexane, octanol and POPC, respectively, for sidechain analogs and Wimley-White peptides. These experimental values serve as important anchor points in choosing between alternate CG models based on their observed permeation profiles, particularly for Arg, Lys and Gln residues where the all-atom OPLS solvation energy does not agree well with experiment. Available partitioning data was also used to reparameterize the representation of the peptide backbone, which needed to be made less attractive for the bilayer hydrophobic core region. The newly developed force field, CgProt 2.4, correctly predicts the global energy minimum in the potentials of mean force for insertion of the uncharged membrane-associated peptides LS3 and WALP23. CgProt will find application in studies of lipid-protein interactions and the conformational properties of diverse membrane protein systems.
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The ADD Force Field for Sugars and Polyols: Predicting the Additivity of Protein-Osmolyte Interaction
The protein-osmolyte interaction has been shown experimentally to follow an additive construct, where the individual osmolyte-backbone and osmolyte-sidechains 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-sidechain 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, as well as their interaction with water. The accurate description of the separate osmolyte-backbone and osmolyte-sidechain 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.
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- Award ID(s):
- 1716956
- PAR ID:
- 10184396
- Date Published:
- Journal Name:
- The Journal of Physical Chemistry B
- ISSN:
- 1520-6106
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1021/acs.jpcb.0c05345
