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Balanced Protein-Water Interactions Improve Properties of Disordered Proteins and Non-Specific Protein Association.

Best RB, Zheng W, Mittal J - J Chem Theory Comput (2014)

Bottom Line: The modification also results in more realistic protein-protein affinities, and average solvation free energies of model compounds which are more consistent with experiment.Most importantly, we show that this scaling is small enough not to affect adversely the stability of the folded state, with only a modest effect on the stability of model peptides forming α-helix and β-sheet structures.The proposed adjustment opens the way to more accurate atomistic simulations of proteins, particularly for intrinsically disordered proteins, protein-protein association, and crowded cellular environments.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.

ABSTRACT
Some frequently encountered deficiencies in all-atom molecular simulations, such as nonspecific protein-protein interactions being too strong, and unfolded or disordered states being too collapsed, suggest that proteins are insufficiently well solvated in simulations using current state-of-the-art force fields. To address these issues, we make the simplest possible change, by modifying the short-range protein-water pair interactions, and leaving all the water-water and protein-protein parameters unchanged. We find that a modest strengthening of protein-water interactions is sufficient to recover the correct dimensions of intrinsically disordered or unfolded proteins, as determined by direct comparison with small-angle X-ray scattering (SAXS) and Förster resonance energy transfer (FRET) data. The modification also results in more realistic protein-protein affinities, and average solvation free energies of model compounds which are more consistent with experiment. Most importantly, we show that this scaling is small enough not to affect adversely the stability of the folded state, with only a modest effect on the stability of model peptides forming α-helix and β-sheet structures. The proposed adjustment opens the way to more accurate atomistic simulations of proteins, particularly for intrinsically disordered proteins, protein-protein association, and crowded cellular environments.

No MeSH data available.


ACTR secondary chemicalshifts. Black line: experimental Cα secondary shiftscomputed by subtracting the SPARTA+reference shift60 for a random-coil structure(δrc)from the experimental data.61 Blue symbols: simulated shifts computed using SPARTA+ fromAmber ff03w REMD simulations. Red symbols: corresponding results fromAmber ff03ws simulations. Shaded region lies outside of one σof the shift prediction from experiment. All data are at ∼304K.
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fig3: ACTR secondary chemicalshifts. Black line: experimental Cα secondary shiftscomputed by subtracting the SPARTA+reference shift60 for a random-coil structure(δrc)from the experimental data.61 Blue symbols: simulated shifts computed using SPARTA+ fromAmber ff03w REMD simulations. Red symbols: corresponding results fromAmber ff03ws simulations. Shaded region lies outside of one σof the shift prediction from experiment. All data are at ∼304K.

Mentions: To check the backbone sampling for ACTR, we have also performed chemicalshift calculations using SPARTA+60 to comparewith the experimental shifts for this protein determined by Ebertet al.61 Within the error of the shiftprediction, the shifts calculated from either the Amber ff03w or ff03wssimulations, using the replicas closest to the experimental temperature(Figure 3), are in agreement with the experimentaldata. One can conclude that the peptide is rather disordered, withlittle persistent secondary structure. In this case, it appears thatthe shifts are not particularly sensitive to degree of collapse ofthe chain.


Balanced Protein-Water Interactions Improve Properties of Disordered Proteins and Non-Specific Protein Association.

Best RB, Zheng W, Mittal J - J Chem Theory Comput (2014)

ACTR secondary chemicalshifts. Black line: experimental Cα secondary shiftscomputed by subtracting the SPARTA+reference shift60 for a random-coil structure(δrc)from the experimental data.61 Blue symbols: simulated shifts computed using SPARTA+ fromAmber ff03w REMD simulations. Red symbols: corresponding results fromAmber ff03ws simulations. Shaded region lies outside of one σof the shift prediction from experiment. All data are at ∼304K.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230380&req=5

fig3: ACTR secondary chemicalshifts. Black line: experimental Cα secondary shiftscomputed by subtracting the SPARTA+reference shift60 for a random-coil structure(δrc)from the experimental data.61 Blue symbols: simulated shifts computed using SPARTA+ fromAmber ff03w REMD simulations. Red symbols: corresponding results fromAmber ff03ws simulations. Shaded region lies outside of one σof the shift prediction from experiment. All data are at ∼304K.
Mentions: To check the backbone sampling for ACTR, we have also performed chemicalshift calculations using SPARTA+60 to comparewith the experimental shifts for this protein determined by Ebertet al.61 Within the error of the shiftprediction, the shifts calculated from either the Amber ff03w or ff03wssimulations, using the replicas closest to the experimental temperature(Figure 3), are in agreement with the experimentaldata. One can conclude that the peptide is rather disordered, withlittle persistent secondary structure. In this case, it appears thatthe shifts are not particularly sensitive to degree of collapse ofthe chain.

Bottom Line: The modification also results in more realistic protein-protein affinities, and average solvation free energies of model compounds which are more consistent with experiment.Most importantly, we show that this scaling is small enough not to affect adversely the stability of the folded state, with only a modest effect on the stability of model peptides forming α-helix and β-sheet structures.The proposed adjustment opens the way to more accurate atomistic simulations of proteins, particularly for intrinsically disordered proteins, protein-protein association, and crowded cellular environments.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.

ABSTRACT
Some frequently encountered deficiencies in all-atom molecular simulations, such as nonspecific protein-protein interactions being too strong, and unfolded or disordered states being too collapsed, suggest that proteins are insufficiently well solvated in simulations using current state-of-the-art force fields. To address these issues, we make the simplest possible change, by modifying the short-range protein-water pair interactions, and leaving all the water-water and protein-protein parameters unchanged. We find that a modest strengthening of protein-water interactions is sufficient to recover the correct dimensions of intrinsically disordered or unfolded proteins, as determined by direct comparison with small-angle X-ray scattering (SAXS) and Förster resonance energy transfer (FRET) data. The modification also results in more realistic protein-protein affinities, and average solvation free energies of model compounds which are more consistent with experiment. Most importantly, we show that this scaling is small enough not to affect adversely the stability of the folded state, with only a modest effect on the stability of model peptides forming α-helix and β-sheet structures. The proposed adjustment opens the way to more accurate atomistic simulations of proteins, particularly for intrinsically disordered proteins, protein-protein association, and crowded cellular environments.

No MeSH data available.