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COFFDROP: A Coarse-Grained Nonbonded Force Field for Proteins Derived from All-Atom Explicit-Solvent Molecular Dynamics Simulations of Amino Acids.

Andrews CT, Elcock AH - J Chem Theory Comput (2014)

Bottom Line: In a first test of the force field, it was used to predict the clustering behavior of concentrated amino acid solutions; the predictions were directly compared with the results of corresponding all-atom explicit-solvent MD simulations and found to be in excellent agreement.The anomalously strong intermolecular interactions seen in the MD study were reproduced in the COFFDROP simulations; a simple scaling of COFFDROP's nonbonded parameters, however, produced results in better accordance with experiment.Overall, our results suggest that potential functions derived from simulations of pairwise amino acid interactions might be of quite broad applicability, with COFFDROP likely to be especially useful for modeling unfolded or intrinsically disordered proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Iowa , Iowa City, Iowa 52242, United States.

ABSTRACT
We describe the derivation of a set of bonded and nonbonded coarse-grained (CG) potential functions for use in implicit-solvent Brownian dynamics (BD) simulations of proteins derived from all-atom explicit-solvent molecular dynamics (MD) simulations of amino acids. Bonded potential functions were derived from 1 μs MD simulations of each of the 20 canonical amino acids, with histidine modeled in both its protonated and neutral forms; nonbonded potential functions were derived from 1 μs MD simulations of every possible pairing of the amino acids (231 different systems). The angle and dihedral probability distributions and radial distribution functions sampled during MD were used to optimize a set of CG potential functions through use of the iterative Boltzmann inversion (IBI) method. The optimized set of potential functions-which we term COFFDROP (COarse-grained Force Field for Dynamic Representation Of Proteins)-quantitatively reproduced all of the "target" MD distributions. In a first test of the force field, it was used to predict the clustering behavior of concentrated amino acid solutions; the predictions were directly compared with the results of corresponding all-atom explicit-solvent MD simulations and found to be in excellent agreement. In a second test, BD simulations of the small protein villin headpiece were carried out at concentrations that have recently been studied in all-atom explicit-solvent MD simulations by Petrov and Zagrovic (PLoS Comput. Biol. 2014, 5, e1003638). The anomalously strong intermolecular interactions seen in the MD study were reproduced in the COFFDROP simulations; a simple scaling of COFFDROP's nonbonded parameters, however, produced results in better accordance with experiment. Overall, our results suggest that potential functions derived from simulations of pairwise amino acid interactions might be of quite broad applicability, with COFFDROP likely to be especially useful for modeling unfolded or intrinsically disordered proteins.

No MeSH data available.


Clusteringof villin headpiece solutions at a 9.2 mM concentrationin BD. (A) Plot shows the fraction of villin headpiece molecules thatare members of clusters of various sizes. Blue circles represent resultsusing a 1.0 scaling factor with COFFDROP’s nonbonded potentialfunctions, green upward triangles represent results using a 0.9 scalingfactor, yellow downward triangles represent results using a 0.8 scalingfactor, and red squares represent results using a 0.8 scaling factorand starting from a structure in which the villin molecules were alreadyaggregated into a trimer and pentamer. (B) Image showing aggregatedvillin molecules obtained at the end of a 200 ns BD simulation usinga 1.0 scaling factor. Each color represents a different villin molecule.(C) Image showing villin molecules at the end of a 200 ns BD simulationusing a 0.8 scaling factor.
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fig8: Clusteringof villin headpiece solutions at a 9.2 mM concentrationin BD. (A) Plot shows the fraction of villin headpiece molecules thatare members of clusters of various sizes. Blue circles represent resultsusing a 1.0 scaling factor with COFFDROP’s nonbonded potentialfunctions, green upward triangles represent results using a 0.9 scalingfactor, yellow downward triangles represent results using a 0.8 scalingfactor, and red squares represent results using a 0.8 scaling factorand starting from a structure in which the villin molecules were alreadyaggregated into a trimer and pentamer. (B) Image showing aggregatedvillin molecules obtained at the end of a 200 ns BD simulation usinga 1.0 scaling factor. Each color represents a different villin molecule.(C) Image showing villin molecules at the end of a 200 ns BD simulationusing a 0.8 scaling factor.

Mentions: After determining that COFFDROP’snonbonded potential functionswere able to reproduce the clustering behavior of concentrated aminoacid solutions, we carried out a preliminary examination of theirability to describe a weak protein–protein interaction. Thesystem we chose to simulate was a 9.2 mM solution of the villin headpieceprotein that has been the subject of a recent comprehensive MD studyby Petrov and Zagrovic.1 These authorsshowed that with all tested MD force fields, aggregation of villinheadpiece molecules occurs at a concentration of 9.2 mM during thecourse of a 50 ns MD simulation; experimentally, however, there isevidence to suggest that no significant aggregation occurs at thisprotein concentration.101 We found thatwhen using COFFDROP’s nonbonded potential functions in ourown simulations of the villin headpiece, significant aggregation occurredon the 50 ns time scale, just as it did using the Amber ff99SB-ILDNforce field (and others) in Petrov and Zagrovic’s study (Figure 8A; blue circles); a view of the aggregated systemis shown in Figure 8B. Continuing the COFFDROPsimulation for an additional 150 ns did not reverse this aggregation.


COFFDROP: A Coarse-Grained Nonbonded Force Field for Proteins Derived from All-Atom Explicit-Solvent Molecular Dynamics Simulations of Amino Acids.

Andrews CT, Elcock AH - J Chem Theory Comput (2014)

Clusteringof villin headpiece solutions at a 9.2 mM concentrationin BD. (A) Plot shows the fraction of villin headpiece molecules thatare members of clusters of various sizes. Blue circles represent resultsusing a 1.0 scaling factor with COFFDROP’s nonbonded potentialfunctions, green upward triangles represent results using a 0.9 scalingfactor, yellow downward triangles represent results using a 0.8 scalingfactor, and red squares represent results using a 0.8 scaling factorand starting from a structure in which the villin molecules were alreadyaggregated into a trimer and pentamer. (B) Image showing aggregatedvillin molecules obtained at the end of a 200 ns BD simulation usinga 1.0 scaling factor. Each color represents a different villin molecule.(C) Image showing villin molecules at the end of a 200 ns BD simulationusing a 0.8 scaling factor.
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Related In: Results  -  Collection

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Show All Figures
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fig8: Clusteringof villin headpiece solutions at a 9.2 mM concentrationin BD. (A) Plot shows the fraction of villin headpiece molecules thatare members of clusters of various sizes. Blue circles represent resultsusing a 1.0 scaling factor with COFFDROP’s nonbonded potentialfunctions, green upward triangles represent results using a 0.9 scalingfactor, yellow downward triangles represent results using a 0.8 scalingfactor, and red squares represent results using a 0.8 scaling factorand starting from a structure in which the villin molecules were alreadyaggregated into a trimer and pentamer. (B) Image showing aggregatedvillin molecules obtained at the end of a 200 ns BD simulation usinga 1.0 scaling factor. Each color represents a different villin molecule.(C) Image showing villin molecules at the end of a 200 ns BD simulationusing a 0.8 scaling factor.
Mentions: After determining that COFFDROP’snonbonded potential functionswere able to reproduce the clustering behavior of concentrated aminoacid solutions, we carried out a preliminary examination of theirability to describe a weak protein–protein interaction. Thesystem we chose to simulate was a 9.2 mM solution of the villin headpieceprotein that has been the subject of a recent comprehensive MD studyby Petrov and Zagrovic.1 These authorsshowed that with all tested MD force fields, aggregation of villinheadpiece molecules occurs at a concentration of 9.2 mM during thecourse of a 50 ns MD simulation; experimentally, however, there isevidence to suggest that no significant aggregation occurs at thisprotein concentration.101 We found thatwhen using COFFDROP’s nonbonded potential functions in ourown simulations of the villin headpiece, significant aggregation occurredon the 50 ns time scale, just as it did using the Amber ff99SB-ILDNforce field (and others) in Petrov and Zagrovic’s study (Figure 8A; blue circles); a view of the aggregated systemis shown in Figure 8B. Continuing the COFFDROPsimulation for an additional 150 ns did not reverse this aggregation.

Bottom Line: In a first test of the force field, it was used to predict the clustering behavior of concentrated amino acid solutions; the predictions were directly compared with the results of corresponding all-atom explicit-solvent MD simulations and found to be in excellent agreement.The anomalously strong intermolecular interactions seen in the MD study were reproduced in the COFFDROP simulations; a simple scaling of COFFDROP's nonbonded parameters, however, produced results in better accordance with experiment.Overall, our results suggest that potential functions derived from simulations of pairwise amino acid interactions might be of quite broad applicability, with COFFDROP likely to be especially useful for modeling unfolded or intrinsically disordered proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Iowa , Iowa City, Iowa 52242, United States.

ABSTRACT
We describe the derivation of a set of bonded and nonbonded coarse-grained (CG) potential functions for use in implicit-solvent Brownian dynamics (BD) simulations of proteins derived from all-atom explicit-solvent molecular dynamics (MD) simulations of amino acids. Bonded potential functions were derived from 1 μs MD simulations of each of the 20 canonical amino acids, with histidine modeled in both its protonated and neutral forms; nonbonded potential functions were derived from 1 μs MD simulations of every possible pairing of the amino acids (231 different systems). The angle and dihedral probability distributions and radial distribution functions sampled during MD were used to optimize a set of CG potential functions through use of the iterative Boltzmann inversion (IBI) method. The optimized set of potential functions-which we term COFFDROP (COarse-grained Force Field for Dynamic Representation Of Proteins)-quantitatively reproduced all of the "target" MD distributions. In a first test of the force field, it was used to predict the clustering behavior of concentrated amino acid solutions; the predictions were directly compared with the results of corresponding all-atom explicit-solvent MD simulations and found to be in excellent agreement. In a second test, BD simulations of the small protein villin headpiece were carried out at concentrations that have recently been studied in all-atom explicit-solvent MD simulations by Petrov and Zagrovic (PLoS Comput. Biol. 2014, 5, e1003638). The anomalously strong intermolecular interactions seen in the MD study were reproduced in the COFFDROP simulations; a simple scaling of COFFDROP's nonbonded parameters, however, produced results in better accordance with experiment. Overall, our results suggest that potential functions derived from simulations of pairwise amino acid interactions might be of quite broad applicability, with COFFDROP likely to be especially useful for modeling unfolded or intrinsically disordered proteins.

No MeSH data available.