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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.


Peptide folding equilibria. (A) Temperature-dependenthelix formationin Ac-(AAQAA)3-NH2, (inset) per-residue fractionhelix at 300 K. (B) Folded population of Trp Cage. (C) Folded populationof GB1 hairpin. (D) Folded population of chignolin. Folded populationsare defined as those with dRMS from theexperimental structure of less than 0.2 nm. Green symbols indicateAmber ff03ws, and where applicable, red symbols indicate Amber ff03wand blue symbols Amber ff03* with TIP3P water. Experimental data areindicated by black lines (taken from Shalongo et al.75 for Ac-(AAQAA)3-NH2, from Muñozet al. for GB1, from Neidigh et al. for Trp cage76 and from from Honda et al. for chignolin77). Up triangles and down triangles refer, respectively,to REMD simulations initiated from unfolded or folded structures.Simulation lengths were 150 ns (50 ns equilibration) for Ac-(AAQAA)3-NH2, 150 ns (75 ns equilibration) for Trp cageinitiated from folded structures, 300 ns (150 ns equilibration) forTrp cage initiated from unfolded structures, 500 ns (200 ns equilibration)for GB1 initiated from folded structures, 400 ns (200 ns equilibration)for GB1 initiated from unfolded structures, and 100 ns (50 ns equilibration)for chignolin.
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fig5: Peptide folding equilibria. (A) Temperature-dependenthelix formationin Ac-(AAQAA)3-NH2, (inset) per-residue fractionhelix at 300 K. (B) Folded population of Trp Cage. (C) Folded populationof GB1 hairpin. (D) Folded population of chignolin. Folded populationsare defined as those with dRMS from theexperimental structure of less than 0.2 nm. Green symbols indicateAmber ff03ws, and where applicable, red symbols indicate Amber ff03wand blue symbols Amber ff03* with TIP3P water. Experimental data areindicated by black lines (taken from Shalongo et al.75 for Ac-(AAQAA)3-NH2, from Muñozet al. for GB1, from Neidigh et al. for Trp cage76 and from from Honda et al. for chignolin77). Up triangles and down triangles refer, respectively,to REMD simulations initiated from unfolded or folded structures.Simulation lengths were 150 ns (50 ns equilibration) for Ac-(AAQAA)3-NH2, 150 ns (75 ns equilibration) for Trp cageinitiated from folded structures, 300 ns (150 ns equilibration) forTrp cage initiated from unfolded structures, 500 ns (200 ns equilibration)for GB1 initiated from folded structures, 400 ns (200 ns equilibration)for GB1 initiated from unfolded structures, and 100 ns (50 ns equilibration)for chignolin.

Mentions: Good sampling of intrinsic backbonepropensity in unstructured peptidesis clearly desirable, but it is also critical that a modificationof the water–protein interaction does not destabilize foldedmotifs such as helices, which may be weakly populated in unfoldedstates. As a model system, we use the 15-residue helix-forming peptideAc-(AAQAA)3-NH2, which forms ∼30% helixat 300 K, and for which the temperature-dependent helix propensityhas been determined by NMR.75 We have previouslyused this as a probe for helix propensity in force fields.6,9,20 In Figure 5A, we show the temperature-dependent helix propensity for this peptideusing Amber03ws, compared with the closely related force-fields Amber03*and Amber03w. It is clear that even with the modified water interactions,stable helical structures are still formed. The overall helix stabilityis reduced in Amber ff03ws, but since it was originally slightly toohigh in Amber ff03w at low temperatures, the agreement with experimentis somewhat improved at 300 K (see per-residue helix populations inFigure 5A, inset).


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)

Peptide folding equilibria. (A) Temperature-dependenthelix formationin Ac-(AAQAA)3-NH2, (inset) per-residue fractionhelix at 300 K. (B) Folded population of Trp Cage. (C) Folded populationof GB1 hairpin. (D) Folded population of chignolin. Folded populationsare defined as those with dRMS from theexperimental structure of less than 0.2 nm. Green symbols indicateAmber ff03ws, and where applicable, red symbols indicate Amber ff03wand blue symbols Amber ff03* with TIP3P water. Experimental data areindicated by black lines (taken from Shalongo et al.75 for Ac-(AAQAA)3-NH2, from Muñozet al. for GB1, from Neidigh et al. for Trp cage76 and from from Honda et al. for chignolin77). Up triangles and down triangles refer, respectively,to REMD simulations initiated from unfolded or folded structures.Simulation lengths were 150 ns (50 ns equilibration) for Ac-(AAQAA)3-NH2, 150 ns (75 ns equilibration) for Trp cageinitiated from folded structures, 300 ns (150 ns equilibration) forTrp cage initiated from unfolded structures, 500 ns (200 ns equilibration)for GB1 initiated from folded structures, 400 ns (200 ns equilibration)for GB1 initiated from unfolded structures, and 100 ns (50 ns equilibration)for chignolin.
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fig5: Peptide folding equilibria. (A) Temperature-dependenthelix formationin Ac-(AAQAA)3-NH2, (inset) per-residue fractionhelix at 300 K. (B) Folded population of Trp Cage. (C) Folded populationof GB1 hairpin. (D) Folded population of chignolin. Folded populationsare defined as those with dRMS from theexperimental structure of less than 0.2 nm. Green symbols indicateAmber ff03ws, and where applicable, red symbols indicate Amber ff03wand blue symbols Amber ff03* with TIP3P water. Experimental data areindicated by black lines (taken from Shalongo et al.75 for Ac-(AAQAA)3-NH2, from Muñozet al. for GB1, from Neidigh et al. for Trp cage76 and from from Honda et al. for chignolin77). Up triangles and down triangles refer, respectively,to REMD simulations initiated from unfolded or folded structures.Simulation lengths were 150 ns (50 ns equilibration) for Ac-(AAQAA)3-NH2, 150 ns (75 ns equilibration) for Trp cageinitiated from folded structures, 300 ns (150 ns equilibration) forTrp cage initiated from unfolded structures, 500 ns (200 ns equilibration)for GB1 initiated from folded structures, 400 ns (200 ns equilibration)for GB1 initiated from unfolded structures, and 100 ns (50 ns equilibration)for chignolin.
Mentions: Good sampling of intrinsic backbonepropensity in unstructured peptidesis clearly desirable, but it is also critical that a modificationof the water–protein interaction does not destabilize foldedmotifs such as helices, which may be weakly populated in unfoldedstates. As a model system, we use the 15-residue helix-forming peptideAc-(AAQAA)3-NH2, which forms ∼30% helixat 300 K, and for which the temperature-dependent helix propensityhas been determined by NMR.75 We have previouslyused this as a probe for helix propensity in force fields.6,9,20 In Figure 5A, we show the temperature-dependent helix propensity for this peptideusing Amber03ws, compared with the closely related force-fields Amber03*and Amber03w. It is clear that even with the modified water interactions,stable helical structures are still formed. The overall helix stabilityis reduced in Amber ff03ws, but since it was originally slightly toohigh in Amber ff03w at low temperatures, the agreement with experimentis somewhat improved at 300 K (see per-residue helix populations inFigure 5A, inset).

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.