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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.


Related in: MedlinePlus

Radial distribution functions of amino acid pairs and amino aciddendrogram calculated from all-atom MD. (A) Plot showing 231 Cα–Cα g(r) functions. (B) Dendrogram createdby performing agglomerative clustering on the calculated correlationcoefficients of the 231 Cα–Cα g(r) functions shown in A. (C) Plot showing 231 g(r) functions calculated using only theclosest distance between any pair of heavy atoms.
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fig2: Radial distribution functions of amino acid pairs and amino aciddendrogram calculated from all-atom MD. (A) Plot showing 231 Cα–Cα g(r) functions. (B) Dendrogram createdby performing agglomerative clustering on the calculated correlationcoefficients of the 231 Cα–Cα g(r) functions shown in A. (C) Plot showing 231 g(r) functions calculated using only theclosest distance between any pair of heavy atoms.

Mentions: Of more direct relevance to the remainder of the presentwork isthe fact that the 231 × 1 μs MD simulations provide uswith meaningful estimates of the association thermodynamics for allpossible pairings of the amino acids. A simple way to gauge the interactionsof different amino acid pairs is to compare their radial distributionfunctions (g(r)) computed usingthe Cα–Cα distance of each MD snapshot. Such aplot is shown in Figure 2A, from which it canbe seen that significant interactions are apparent even at quite longCα–Cα separation distances. More importantly, wecan use these g(r)s to group aminoacids according to the similarity of their interactions with otheramino acids (see Methods); a dendrogram constructedon the basis of the computed Cα–Cα g(r) data is shown in Figure 2B. Encouragingly, it can be seen that amino acids that are knownto share physicochemical similarities automatically group with oneanother in the dendrogram: in particular, the aliphatic, aromatic,acidic, and basic amino acids generally tend to form separate clusters.The groupings are not perfect, however, as gly surprisingly groupswith the positively charged amino acids, thr is grouped with the aliphaticamino acids, and protonated his (hip) is more closely grouped withthe negative amino acids than the positive amino acids. Overall, however,the dendrogram suggests that the g(r)s obtained from the MD simulations are sufficiently reliable—andcontain sufficient information—to draw meaningful conclusionsabout the nature of amino acids’ interactions with other aminoacids.


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)

Radial distribution functions of amino acid pairs and amino aciddendrogram calculated from all-atom MD. (A) Plot showing 231 Cα–Cα g(r) functions. (B) Dendrogram createdby performing agglomerative clustering on the calculated correlationcoefficients of the 231 Cα–Cα g(r) functions shown in A. (C) Plot showing 231 g(r) functions calculated using only theclosest distance between any pair of heavy atoms.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230375&req=5

fig2: Radial distribution functions of amino acid pairs and amino aciddendrogram calculated from all-atom MD. (A) Plot showing 231 Cα–Cα g(r) functions. (B) Dendrogram createdby performing agglomerative clustering on the calculated correlationcoefficients of the 231 Cα–Cα g(r) functions shown in A. (C) Plot showing 231 g(r) functions calculated using only theclosest distance between any pair of heavy atoms.
Mentions: Of more direct relevance to the remainder of the presentwork isthe fact that the 231 × 1 μs MD simulations provide uswith meaningful estimates of the association thermodynamics for allpossible pairings of the amino acids. A simple way to gauge the interactionsof different amino acid pairs is to compare their radial distributionfunctions (g(r)) computed usingthe Cα–Cα distance of each MD snapshot. Such aplot is shown in Figure 2A, from which it canbe seen that significant interactions are apparent even at quite longCα–Cα separation distances. More importantly, wecan use these g(r)s to group aminoacids according to the similarity of their interactions with otheramino acids (see Methods); a dendrogram constructedon the basis of the computed Cα–Cα g(r) data is shown in Figure 2B. Encouragingly, it can be seen that amino acids that are knownto share physicochemical similarities automatically group with oneanother in the dendrogram: in particular, the aliphatic, aromatic,acidic, and basic amino acids generally tend to form separate clusters.The groupings are not perfect, however, as gly surprisingly groupswith the positively charged amino acids, thr is grouped with the aliphaticamino acids, and protonated his (hip) is more closely grouped withthe negative amino acids than the positive amino acids. Overall, however,the dendrogram suggests that the g(r)s obtained from the MD simulations are sufficiently reliable—andcontain sufficient information—to draw meaningful conclusionsabout the nature of amino acids’ interactions with other aminoacids.

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.


Related in: MedlinePlus