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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.


Properties of the intrinsically disordered protein ACTR. SAXS intensityprofiles from experiment (black)53 andfrom simulations using Amber ff03w (red) and Amber ff03ws (green)are shown for (A) temperatures of 278 and (B) 318 K at an ionic strengthof ∼250 mM (close to the experimental conditions.53 In panels C and D, we show the distributionsof radius of gyration at 278 and 318 K, respectively. REMD simulationswere performed for 100 ns per replica using a 6.5 nm truncated octahedronbox. Prior to this, equilibration runs of 10 and 30 ns were performedfor Amber ff03w and ff03ws, respectively.
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fig2: Properties of the intrinsically disordered protein ACTR. SAXS intensityprofiles from experiment (black)53 andfrom simulations using Amber ff03w (red) and Amber ff03ws (green)are shown for (A) temperatures of 278 and (B) 318 K at an ionic strengthof ∼250 mM (close to the experimental conditions.53 In panels C and D, we show the distributionsof radius of gyration at 278 and 318 K, respectively. REMD simulationswere performed for 100 ns per replica using a 6.5 nm truncated octahedronbox. Prior to this, equilibration runs of 10 and 30 ns were performedfor Amber ff03w and ff03ws, respectively.

Mentions: While theagreement for Csp M34 is good, it is a relatively short chain, anda specific case. A possible concern could be that we optimized ourforce field for a particular chain length or sequence composition,while it may fail for others. This concern arises because of the fundamentaldifferences in the hydrophobic effect on different length scales,17 and the known effects of sequence compositionand patterning on the dimensions of unfolded proteins.55−58 Kjaergaard et al.53 have measured thedimensions of the intrinsically disordered protein ACTR by SAXS attwo temperatures. They found that the protein collapses slightly withincreasing temperature, with the average Rg decreasing from 2.63 nm at 278 K to 2.39 nm at 318 K. We have performedreplica-exchange molecular dynamics simulations on the same ACTR sequence,using the same system size and replica spacing as for the labeledCsp M34. The average radii of gyration from the replicas at 278 and318 K are 2.13 (0.8) and 2.03 (0.4) nm, respectively using Amber ff03wsand 1.56 (0.1) and 1.51 (0.2) nm at 278 and 318 K using Amber ff03w.Since the experimental Rg is inferredfrom a model, we have also directly calculated the scattering intensityusing CRYSOL,59 and averaged over the trajectory.In Figure 2, we show a comparison of the experimentaland calculated scattering intensity profiles at the two temperaturesstudied in experiment, 278 and 318 K. The match to the experimentaldata (black curve) is much improved with the new force field usingscaled protein–water interactions (green curve) relative tothe Amber ff03w force field (red curve), although the curves fromthe simulation data still indicate that the structural ensemble isslightly more compact relative to the experimental data. A likelyreason for the this remaining discrepancy may be the excluded volumeeffects due to the limited system size utilized to make the replicaexchange simulations computationally feasible. A simple calculationusing a Gaussian chain model suggests that the magnitude of this effectis comparable to the amount by which the simulation Rg is reduced, relative to the experimental estimate.


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)

Properties of the intrinsically disordered protein ACTR. SAXS intensityprofiles from experiment (black)53 andfrom simulations using Amber ff03w (red) and Amber ff03ws (green)are shown for (A) temperatures of 278 and (B) 318 K at an ionic strengthof ∼250 mM (close to the experimental conditions.53 In panels C and D, we show the distributionsof radius of gyration at 278 and 318 K, respectively. REMD simulationswere performed for 100 ns per replica using a 6.5 nm truncated octahedronbox. Prior to this, equilibration runs of 10 and 30 ns were performedfor Amber ff03w and ff03ws, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Properties of the intrinsically disordered protein ACTR. SAXS intensityprofiles from experiment (black)53 andfrom simulations using Amber ff03w (red) and Amber ff03ws (green)are shown for (A) temperatures of 278 and (B) 318 K at an ionic strengthof ∼250 mM (close to the experimental conditions.53 In panels C and D, we show the distributionsof radius of gyration at 278 and 318 K, respectively. REMD simulationswere performed for 100 ns per replica using a 6.5 nm truncated octahedronbox. Prior to this, equilibration runs of 10 and 30 ns were performedfor Amber ff03w and ff03ws, respectively.
Mentions: While theagreement for Csp M34 is good, it is a relatively short chain, anda specific case. A possible concern could be that we optimized ourforce field for a particular chain length or sequence composition,while it may fail for others. This concern arises because of the fundamentaldifferences in the hydrophobic effect on different length scales,17 and the known effects of sequence compositionand patterning on the dimensions of unfolded proteins.55−58 Kjaergaard et al.53 have measured thedimensions of the intrinsically disordered protein ACTR by SAXS attwo temperatures. They found that the protein collapses slightly withincreasing temperature, with the average Rg decreasing from 2.63 nm at 278 K to 2.39 nm at 318 K. We have performedreplica-exchange molecular dynamics simulations on the same ACTR sequence,using the same system size and replica spacing as for the labeledCsp M34. The average radii of gyration from the replicas at 278 and318 K are 2.13 (0.8) and 2.03 (0.4) nm, respectively using Amber ff03wsand 1.56 (0.1) and 1.51 (0.2) nm at 278 and 318 K using Amber ff03w.Since the experimental Rg is inferredfrom a model, we have also directly calculated the scattering intensityusing CRYSOL,59 and averaged over the trajectory.In Figure 2, we show a comparison of the experimentaland calculated scattering intensity profiles at the two temperaturesstudied in experiment, 278 and 318 K. The match to the experimentaldata (black curve) is much improved with the new force field usingscaled protein–water interactions (green curve) relative tothe Amber ff03w force field (red curve), although the curves fromthe simulation data still indicate that the structural ensemble isslightly more compact relative to the experimental data. A likelyreason for the this remaining discrepancy may be the excluded volumeeffects due to the limited system size utilized to make the replicaexchange simulations computationally feasible. A simple calculationusing a Gaussian chain model suggests that the magnitude of this effectis comparable to the amount by which the simulation Rg is reduced, relative to the experimental estimate.

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.