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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.


Clustering of alanine,leucine, asparagine, and tryptophan solutionsin MD and BD. The plots show the fraction of solute molecules thatare members of clusters of various sizes. Blue circles represent resultsfrom MD, green upward triangles represent results from BD using COFFDROP,and red downward triangles represent results from BD using stericnonbonded potentials.
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fig6: Clustering of alanine,leucine, asparagine, and tryptophan solutionsin MD and BD. The plots show the fraction of solute molecules thatare members of clusters of various sizes. Blue circles represent resultsfrom MD, green upward triangles represent results from BD using COFFDROP,and red downward triangles represent results from BD using stericnonbonded potentials.

Mentions: The nonbonded potential functionsthat we have derived are pairwiseterms that have been optimized to reproduce interactions between pairsof amino acids. The ultimate application of such potential functions,however, is to protein systems, which are obviously considerably morecomplicated than the systems studied above. One way to assess initiallywhether the pairwise interaction functions might work for more complicatedsystems is to carry out comparative (all-atom) MD and (coarse-grained)BD simulations of systems where three-body and higher interactionsare unavoidable. To do this, we performed an additional series of1 μs MD simulations of systems containing 3 or 4 copies of eachof the following (capped) amino acids: ala, asn, asp, cys, gly, leu,lys, tyr, trp, and val; these systems were selected so as to providea broad sampling of different physicochemical characteristics. Thelevel of agreement between the MD and BD simulations was determinedby performing a cluster analysis of the snapshots sampled during thesimulations (see Methods); the results ofsuch analyses are shown in Figure 6. The MDsimulation data (blue symbols) show that populations of monomers,dimers, trimers and (in the case of 4-copy simulations) tetramersare observed in each simulation; the results for the tryptophan systems,for example, (far right of Figure 6), showthat they are considerably more prone to forming higher-order clustersthan more weakly interacting amino acids such as alanine (far leftof Figure 6). More importantly, however, thedistributions of the various cluster sizes obtained from the all-atomMD simulations are found to be well reproduced by the BD simulationsusing the CG nonbonded potential functions (green symbols): the (representative)results for the ala, leu, asn, and trp systems are shown in Figure 6, while the results for the other amino acids studiedare shown in Supporting Information Figure S11. To verify that reproducing the clustering behavior seen in MD isnot a trivial consequence of adding more amino acids to the simulationbox, additional BD simulations were performed using purely stericnonbonded potentials (red symbols) and were found to be unable toreproduce the clustering behavior observed in MD.


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)

Clustering of alanine,leucine, asparagine, and tryptophan solutionsin MD and BD. The plots show the fraction of solute molecules thatare members of clusters of various sizes. Blue circles represent resultsfrom MD, green upward triangles represent results from BD using COFFDROP,and red downward triangles represent results from BD using stericnonbonded potentials.
© Copyright Policy
Related In: Results  -  Collection

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fig6: Clustering of alanine,leucine, asparagine, and tryptophan solutionsin MD and BD. The plots show the fraction of solute molecules thatare members of clusters of various sizes. Blue circles represent resultsfrom MD, green upward triangles represent results from BD using COFFDROP,and red downward triangles represent results from BD using stericnonbonded potentials.
Mentions: The nonbonded potential functionsthat we have derived are pairwiseterms that have been optimized to reproduce interactions between pairsof amino acids. The ultimate application of such potential functions,however, is to protein systems, which are obviously considerably morecomplicated than the systems studied above. One way to assess initiallywhether the pairwise interaction functions might work for more complicatedsystems is to carry out comparative (all-atom) MD and (coarse-grained)BD simulations of systems where three-body and higher interactionsare unavoidable. To do this, we performed an additional series of1 μs MD simulations of systems containing 3 or 4 copies of eachof the following (capped) amino acids: ala, asn, asp, cys, gly, leu,lys, tyr, trp, and val; these systems were selected so as to providea broad sampling of different physicochemical characteristics. Thelevel of agreement between the MD and BD simulations was determinedby performing a cluster analysis of the snapshots sampled during thesimulations (see Methods); the results ofsuch analyses are shown in Figure 6. The MDsimulation data (blue symbols) show that populations of monomers,dimers, trimers and (in the case of 4-copy simulations) tetramersare observed in each simulation; the results for the tryptophan systems,for example, (far right of Figure 6), showthat they are considerably more prone to forming higher-order clustersthan more weakly interacting amino acids such as alanine (far leftof Figure 6). More importantly, however, thedistributions of the various cluster sizes obtained from the all-atomMD simulations are found to be well reproduced by the BD simulationsusing the CG nonbonded potential functions (green symbols): the (representative)results for the ala, leu, asn, and trp systems are shown in Figure 6, while the results for the other amino acids studiedare shown in Supporting Information Figure S11. To verify that reproducing the clustering behavior seen in MD isnot a trivial consequence of adding more amino acids to the simulationbox, additional BD simulations were performed using purely stericnonbonded potentials (red symbols) and were found to be unable toreproduce the clustering behavior observed in MD.

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.