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Systematic validation of protein force fields against experimental data.

Lindorff-Larsen K, Maragakis P, Piana S, Eastwood MP, Dror RO, Shaw DE - PLoS ONE (2012)

Bottom Line: Here we present a systematic and extensive evaluation of eight different protein force fields based on comparisons of experimental data with molecular dynamics simulations that reach a previously inaccessible timescale.Third, we tested the force fields' abilities to fold two small proteins--one α-helical, the other with β-sheet structure.The results suggest that force fields have improved over time, and that the most recent versions, while not perfect, provide an accurate description of many structural and dynamical properties of proteins.

View Article: PubMed Central - PubMed

Affiliation: DE Shaw Research, New York, New York, United States of America.

ABSTRACT
Molecular dynamics simulations provide a vehicle for capturing the structures, motions, and interactions of biological macromolecules in full atomic detail. The accuracy of such simulations, however, is critically dependent on the force field--the mathematical model used to approximate the atomic-level forces acting on the simulated molecular system. Here we present a systematic and extensive evaluation of eight different protein force fields based on comparisons of experimental data with molecular dynamics simulations that reach a previously inaccessible timescale. First, through extensive comparisons with experimental NMR data, we examined the force fields' abilities to describe the structure and fluctuations of folded proteins. Second, we quantified potential biases towards different secondary structure types by comparing experimental and simulation data for small peptides that preferentially populate either helical or sheet-like structures. Third, we tested the force fields' abilities to fold two small proteins--one α-helical, the other with β-sheet structure. The results suggest that force fields have improved over time, and that the most recent versions, while not perfect, provide an accurate description of many structural and dynamical properties of proteins.

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Comparison between calculated and experimental secondary structure propensities.In (a), we show the helical fraction of the (AAQAA)3 15-mer peptide in simulations and experiment as a function of temperature. In (b), we show the fraction folded of the CLN025 10-residue peptide in simulations and experiments as a function of temperature.
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pone-0032131-g002: Comparison between calculated and experimental secondary structure propensities.In (a), we show the helical fraction of the (AAQAA)3 15-mer peptide in simulations and experiment as a function of temperature. In (b), we show the fraction folded of the CLN025 10-residue peptide in simulations and experiments as a function of temperature.

Mentions: We thus performed simulations of two small peptide systems with the aim of evaluating how well the eight force fields provide a balance between propensity to form helical, sheet-like, and coil structures. The first test involves a 15-residue peptide consisting of three repeats of the amino acid sequence AAQAA [24]. NMR and circular dichroism measurements suggest that this peptide is ∼45% helical at a temperature of 275 K, and that the helicity has a relatively steep temperature dependency resulting in less than 10% helicity at 320 K. Using 10 µs of simulated tempering MD simulations, we calculated the temperature-dependent fraction of helical structure of the AAQAA peptide in each of the eight force fields (Fig. 2a). The results confirm that the force fields display a broad range of propensities towards forming helical structure, with CHARMM27 and Amber ff03 overstabilizing helices and ff99SB-ILDN understabilizing them. The three “helix coil–balanced” force fields (ff99SB*-ILDN, ff03* and CHARMM22*) all provide a better description of this peptide system. This result is not surprising, however, given that the comparison with the helicity of the AAQAA peptide was part of the optimization procedure used to refine these force fields.


Systematic validation of protein force fields against experimental data.

Lindorff-Larsen K, Maragakis P, Piana S, Eastwood MP, Dror RO, Shaw DE - PLoS ONE (2012)

Comparison between calculated and experimental secondary structure propensities.In (a), we show the helical fraction of the (AAQAA)3 15-mer peptide in simulations and experiment as a function of temperature. In (b), we show the fraction folded of the CLN025 10-residue peptide in simulations and experiments as a function of temperature.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3285199&req=5

pone-0032131-g002: Comparison between calculated and experimental secondary structure propensities.In (a), we show the helical fraction of the (AAQAA)3 15-mer peptide in simulations and experiment as a function of temperature. In (b), we show the fraction folded of the CLN025 10-residue peptide in simulations and experiments as a function of temperature.
Mentions: We thus performed simulations of two small peptide systems with the aim of evaluating how well the eight force fields provide a balance between propensity to form helical, sheet-like, and coil structures. The first test involves a 15-residue peptide consisting of three repeats of the amino acid sequence AAQAA [24]. NMR and circular dichroism measurements suggest that this peptide is ∼45% helical at a temperature of 275 K, and that the helicity has a relatively steep temperature dependency resulting in less than 10% helicity at 320 K. Using 10 µs of simulated tempering MD simulations, we calculated the temperature-dependent fraction of helical structure of the AAQAA peptide in each of the eight force fields (Fig. 2a). The results confirm that the force fields display a broad range of propensities towards forming helical structure, with CHARMM27 and Amber ff03 overstabilizing helices and ff99SB-ILDN understabilizing them. The three “helix coil–balanced” force fields (ff99SB*-ILDN, ff03* and CHARMM22*) all provide a better description of this peptide system. This result is not surprising, however, given that the comparison with the helicity of the AAQAA peptide was part of the optimization procedure used to refine these force fields.

Bottom Line: Here we present a systematic and extensive evaluation of eight different protein force fields based on comparisons of experimental data with molecular dynamics simulations that reach a previously inaccessible timescale.Third, we tested the force fields' abilities to fold two small proteins--one α-helical, the other with β-sheet structure.The results suggest that force fields have improved over time, and that the most recent versions, while not perfect, provide an accurate description of many structural and dynamical properties of proteins.

View Article: PubMed Central - PubMed

Affiliation: DE Shaw Research, New York, New York, United States of America.

ABSTRACT
Molecular dynamics simulations provide a vehicle for capturing the structures, motions, and interactions of biological macromolecules in full atomic detail. The accuracy of such simulations, however, is critically dependent on the force field--the mathematical model used to approximate the atomic-level forces acting on the simulated molecular system. Here we present a systematic and extensive evaluation of eight different protein force fields based on comparisons of experimental data with molecular dynamics simulations that reach a previously inaccessible timescale. First, through extensive comparisons with experimental NMR data, we examined the force fields' abilities to describe the structure and fluctuations of folded proteins. Second, we quantified potential biases towards different secondary structure types by comparing experimental and simulation data for small peptides that preferentially populate either helical or sheet-like structures. Third, we tested the force fields' abilities to fold two small proteins--one α-helical, the other with β-sheet structure. The results suggest that force fields have improved over time, and that the most recent versions, while not perfect, provide an accurate description of many structural and dynamical properties of proteins.

Show MeSH
Related in: MedlinePlus