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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.


Association of villin. The minimum distancebetween two villinHP36 molecules at 8.5 mM total protein concentration is shown for(A) Amber ff03*, (B) Amber ff03w, and (C) Amber ff03ws. Broken redlines indicate the boundaries used to define association and dissociationevents. The dRMS from the native state is shown for (D) Amber ff03*,(E) Amber ff03w, and (F) Amber ff03ws (black, blue curves correspondto the two chains in the system).
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fig4: Association of villin. The minimum distancebetween two villinHP36 molecules at 8.5 mM total protein concentration is shown for(A) Amber ff03*, (B) Amber ff03w, and (C) Amber ff03ws. Broken redlines indicate the boundaries used to define association and dissociationevents. The dRMS from the native state is shown for (D) Amber ff03*,(E) Amber ff03w, and (F) Amber ff03ws (black, blue curves correspondto the two chains in the system).

Mentions: Association of villinHP36 is an appealing test for nonspecific protein-protein affinities,because of its modest size (36 residues) relative to other systemsoften used for studying weak protein association, such as Lysozyme.Villin HP36 has been shown to associate in a diffusion-limited mannerin a recent computational study,27 whileit is known to remain soluble up to ∼1.5 mM,68 based on the invariance of NMR-determined diffusion coefficientsup to that concentration. Therefore, we expect a dissociation constant Kd > 1.5 mM. On the other hand, there is evidencefor weak protein association from a small change in chemical shiftsat a concentration of ∼32 mM.69 Totest the self-interactions of villin, we ran simulations of two villinHP36 molecules at a total protein concentration of ∼8.5 mM,starting from the same initial configuration with the molecules spaced∼1 nm apart. The simulations were run for 200 ns at 300 K.We observed binding and unbinding events from long equilbrium simulations,where we define a binding event as when the minimum distance betweenthe molecules falls below 0.2 nm, and unbinding when it exceeds 1.0nm. These distances were chosen based on the trajectory of minimumdistances, shown in Figure 4. Using these cut-offs,we can compute association and dissociation rates, and dissociationconstants Kd for each force field, shownin Table 3.


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)

Association of villin. The minimum distancebetween two villinHP36 molecules at 8.5 mM total protein concentration is shown for(A) Amber ff03*, (B) Amber ff03w, and (C) Amber ff03ws. Broken redlines indicate the boundaries used to define association and dissociationevents. The dRMS from the native state is shown for (D) Amber ff03*,(E) Amber ff03w, and (F) Amber ff03ws (black, blue curves correspondto the two chains in the system).
© Copyright Policy
Related In: Results  -  Collection

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

fig4: Association of villin. The minimum distancebetween two villinHP36 molecules at 8.5 mM total protein concentration is shown for(A) Amber ff03*, (B) Amber ff03w, and (C) Amber ff03ws. Broken redlines indicate the boundaries used to define association and dissociationevents. The dRMS from the native state is shown for (D) Amber ff03*,(E) Amber ff03w, and (F) Amber ff03ws (black, blue curves correspondto the two chains in the system).
Mentions: Association of villinHP36 is an appealing test for nonspecific protein-protein affinities,because of its modest size (36 residues) relative to other systemsoften used for studying weak protein association, such as Lysozyme.Villin HP36 has been shown to associate in a diffusion-limited mannerin a recent computational study,27 whileit is known to remain soluble up to ∼1.5 mM,68 based on the invariance of NMR-determined diffusion coefficientsup to that concentration. Therefore, we expect a dissociation constant Kd > 1.5 mM. On the other hand, there is evidencefor weak protein association from a small change in chemical shiftsat a concentration of ∼32 mM.69 Totest the self-interactions of villin, we ran simulations of two villinHP36 molecules at a total protein concentration of ∼8.5 mM,starting from the same initial configuration with the molecules spaced∼1 nm apart. The simulations were run for 200 ns at 300 K.We observed binding and unbinding events from long equilbrium simulations,where we define a binding event as when the minimum distance betweenthe molecules falls below 0.2 nm, and unbinding when it exceeds 1.0nm. These distances were chosen based on the trajectory of minimumdistances, shown in Figure 4. Using these cut-offs,we can compute association and dissociation rates, and dissociationconstants Kd for each force field, shownin Table 3.

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.