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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.


Related in: MedlinePlus

Temperature-dependent collapse of the M34 fragment of CspTm. (A)Radius of gyration (excluding chromophores) for ff03w (black symbols)and ff03ws (red symbols). Blue line indicates values estimated fromFRET measurements.48 Red dot-dashed anddashed lines indicate the results obtained by reweighting at γ= 1.05 and 1.15, respectively. (inset) Dependence of radius of gyrationon the water–protein scaling factor γ at 300 K; horizontalblue line indicates the value from FRET and vertical red line the“optimal” choice of γ ≡ 1.10. (B) Separationof chromophores as given by the distance between the gamma sulfuratom of the cysteines to which they are linked (empty symbols) orby the distance between center of mass of the chromophores themselves(solid symbols). Color code as in panel A. (C) FRET efficiency ascomputed from the distances in panel B, meaning of symbols is thesame. Blue line indicates experimental FRET measurements or derivedquantities.48
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fig1: Temperature-dependent collapse of the M34 fragment of CspTm. (A)Radius of gyration (excluding chromophores) for ff03w (black symbols)and ff03ws (red symbols). Blue line indicates values estimated fromFRET measurements.48 Red dot-dashed anddashed lines indicate the results obtained by reweighting at γ= 1.05 and 1.15, respectively. (inset) Dependence of radius of gyrationon the water–protein scaling factor γ at 300 K; horizontalblue line indicates the value from FRET and vertical red line the“optimal” choice of γ ≡ 1.10. (B) Separationof chromophores as given by the distance between the gamma sulfuratom of the cysteines to which they are linked (empty symbols) orby the distance between center of mass of the chromophores themselves(solid symbols). Color code as in panel A. (C) FRET efficiency ascomputed from the distances in panel B, meaning of symbols is thesame. Blue line indicates experimental FRET measurements or derivedquantities.48

Mentions: We have determinedthe temperature dependence of the Csp M34 propertiesvia replica-exchange molecular dynamics (REMD) at constant temperatureand pressure, using 42 replicas spanning a temperature of 275–423K and a 6.5 nm truncated octahedron periodic cell. Each run was for100 ns, discarding the first 50 ns as “equilibration”.In Figure 1 we show a comparison with the temperature-dependentexperimental data, both the average FRET efficiency measured (Figure 1C), as well as the radius of gyration (Rg) inferred from these FRET efficiency measurements (Figure 1A). From the simulation data, we have computed themean FRET efficiency via a simple average over the distance betweenthe chromophores, assuming that the distribution of chromophore orientationsis isotropic at all separations R (i.e., the orientationalfactor κ2 in the FRET transfer rate is ∼2/351,52), and that chromophore dynamics is fast relative to chain dynamics:4The Rg is determinedfrom the simulations, using only the protein atoms (even though thesimulation includes the dye molecules and linkers).


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)

Temperature-dependent collapse of the M34 fragment of CspTm. (A)Radius of gyration (excluding chromophores) for ff03w (black symbols)and ff03ws (red symbols). Blue line indicates values estimated fromFRET measurements.48 Red dot-dashed anddashed lines indicate the results obtained by reweighting at γ= 1.05 and 1.15, respectively. (inset) Dependence of radius of gyrationon the water–protein scaling factor γ at 300 K; horizontalblue line indicates the value from FRET and vertical red line the“optimal” choice of γ ≡ 1.10. (B) Separationof chromophores as given by the distance between the gamma sulfuratom of the cysteines to which they are linked (empty symbols) orby the distance between center of mass of the chromophores themselves(solid symbols). Color code as in panel A. (C) FRET efficiency ascomputed from the distances in panel B, meaning of symbols is thesame. Blue line indicates experimental FRET measurements or derivedquantities.48
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Temperature-dependent collapse of the M34 fragment of CspTm. (A)Radius of gyration (excluding chromophores) for ff03w (black symbols)and ff03ws (red symbols). Blue line indicates values estimated fromFRET measurements.48 Red dot-dashed anddashed lines indicate the results obtained by reweighting at γ= 1.05 and 1.15, respectively. (inset) Dependence of radius of gyrationon the water–protein scaling factor γ at 300 K; horizontalblue line indicates the value from FRET and vertical red line the“optimal” choice of γ ≡ 1.10. (B) Separationof chromophores as given by the distance between the gamma sulfuratom of the cysteines to which they are linked (empty symbols) orby the distance between center of mass of the chromophores themselves(solid symbols). Color code as in panel A. (C) FRET efficiency ascomputed from the distances in panel B, meaning of symbols is thesame. Blue line indicates experimental FRET measurements or derivedquantities.48
Mentions: We have determinedthe temperature dependence of the Csp M34 propertiesvia replica-exchange molecular dynamics (REMD) at constant temperatureand pressure, using 42 replicas spanning a temperature of 275–423K and a 6.5 nm truncated octahedron periodic cell. Each run was for100 ns, discarding the first 50 ns as “equilibration”.In Figure 1 we show a comparison with the temperature-dependentexperimental data, both the average FRET efficiency measured (Figure 1C), as well as the radius of gyration (Rg) inferred from these FRET efficiency measurements (Figure 1A). From the simulation data, we have computed themean FRET efficiency via a simple average over the distance betweenthe chromophores, assuming that the distribution of chromophore orientationsis isotropic at all separations R (i.e., the orientationalfactor κ2 in the FRET transfer rate is ∼2/351,52), and that chromophore dynamics is fast relative to chain dynamics:4The Rg is determinedfrom the simulations, using only the protein atoms (even though thesimulation includes the dye molecules and linkers).

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.


Related in: MedlinePlus