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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.


Spatial disposition of the Cδ pseudoatomof tryptophan inMD and BD. (A–C) Red contours show preferred locations of theCδ pseudoatom of a tryptophan molecule interacting with a secondtryptophan molecule (shown in black) sampled from MD; each of thepanels A–C shows the same image viewed from a different orientation.(D–F) Same as panels A–C, respectively, but showingresults from BD.
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fig9: Spatial disposition of the Cδ pseudoatomof tryptophan inMD and BD. (A–C) Red contours show preferred locations of theCδ pseudoatom of a tryptophan molecule interacting with a secondtryptophan molecule (shown in black) sampled from MD; each of thepanels A–C shows the same image viewed from a different orientation.(D–F) Same as panels A–C, respectively, but showingresults from BD.

Mentions: While the clustering behaviorseen in both the concentrated aminoacid and villin headpiece simulations indicate that COFFDROP’snonbonded potential functions may be useful for modeling concentratedpeptide and protein systems, it is important to note that there isone respect in which the functions perform quite disappointingly.To see this, we return to an analysis of the data obtained from simulationsthat contain only pairs of molecules. It will be recalled from abovethat convergence of the IBI procedure ensures that each of the individualpseudoatom–pseudoatom g(r)s are accurately captured by the CG simulations. However, each ofthe optimized nonbonded potential functions is assumed to be pairwise-additive,that is, independent of the other potential functions; it is thereforepossible that important correlations between potential functions—ifpresent—might not be properly described. A related issue isthat each of the potential functions depends only on the distancebetween two pseudoatoms which means that orientational (angular) preferencesmight also not be correctly captured. It appears to be a disappointingconsequence of these issues that even in simulations of two aminoacid molecules the relative spatial dispositions of pseudoatoms canbe quite poorly described by the CG potential functions. As one exampleof this we show in Figure 9 results for thetryptophan-tryptophan interaction. The contour plots in Figure 9 (A–C) show three different rotational viewsof one of the tryptophan molecules (black), highlighting (in red)the regions of nearby space that are most frequently occupied by theCδ atom of the second tryptophan molecule during MD simulations.Figure 9 (D–F) shows corresponding resultsobtained from BD simulations using our CG potential functions. Whilethere is some degree of similarity between the two sets of results,they are also clearly somewhat different, with some regions of spacethat are occupied during MD not being occupied during BD and viceversa; repeating the analysis with the two tryptophan molecules swappedindicates that these discrepancies are not due to poor sampling ineither the MD or BD (Supporting Information FigureS14). This indicates that while it is possible to correctlyreproduce all of the pseudoatom–pseudoatom g(r)s for CG models of the type developed here, thisdoes not guarantee that the interaction geometries of the parent moleculeswill also be correctly reproduced.


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)

Spatial disposition of the Cδ pseudoatomof tryptophan inMD and BD. (A–C) Red contours show preferred locations of theCδ pseudoatom of a tryptophan molecule interacting with a secondtryptophan molecule (shown in black) sampled from MD; each of thepanels A–C shows the same image viewed from a different orientation.(D–F) Same as panels A–C, respectively, but showingresults from BD.
© Copyright Policy
Related In: Results  -  Collection

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

fig9: Spatial disposition of the Cδ pseudoatomof tryptophan inMD and BD. (A–C) Red contours show preferred locations of theCδ pseudoatom of a tryptophan molecule interacting with a secondtryptophan molecule (shown in black) sampled from MD; each of thepanels A–C shows the same image viewed from a different orientation.(D–F) Same as panels A–C, respectively, but showingresults from BD.
Mentions: While the clustering behaviorseen in both the concentrated aminoacid and villin headpiece simulations indicate that COFFDROP’snonbonded potential functions may be useful for modeling concentratedpeptide and protein systems, it is important to note that there isone respect in which the functions perform quite disappointingly.To see this, we return to an analysis of the data obtained from simulationsthat contain only pairs of molecules. It will be recalled from abovethat convergence of the IBI procedure ensures that each of the individualpseudoatom–pseudoatom g(r)s are accurately captured by the CG simulations. However, each ofthe optimized nonbonded potential functions is assumed to be pairwise-additive,that is, independent of the other potential functions; it is thereforepossible that important correlations between potential functions—ifpresent—might not be properly described. A related issue isthat each of the potential functions depends only on the distancebetween two pseudoatoms which means that orientational (angular) preferencesmight also not be correctly captured. It appears to be a disappointingconsequence of these issues that even in simulations of two aminoacid molecules the relative spatial dispositions of pseudoatoms canbe quite poorly described by the CG potential functions. As one exampleof this we show in Figure 9 results for thetryptophan-tryptophan interaction. The contour plots in Figure 9 (A–C) show three different rotational viewsof one of the tryptophan molecules (black), highlighting (in red)the regions of nearby space that are most frequently occupied by theCδ atom of the second tryptophan molecule during MD simulations.Figure 9 (D–F) shows corresponding resultsobtained from BD simulations using our CG potential functions. Whilethere is some degree of similarity between the two sets of results,they are also clearly somewhat different, with some regions of spacethat are occupied during MD not being occupied during BD and viceversa; repeating the analysis with the two tryptophan molecules swappedindicates that these discrepancies are not due to poor sampling ineither the MD or BD (Supporting Information FigureS14). This indicates that while it is possible to correctlyreproduce all of the pseudoatom–pseudoatom g(r)s for CG models of the type developed here, thisdoes not guarantee that the interaction geometries of the parent moleculeswill also be correctly reproduced.

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.