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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

Derivationof COFFDROP nonbonded potential functions using theIBI method. (A) Plot showing the error in the nonbonded g(r) functions obtained from BD simulations as afunction of IBI iteration number for the ile–leu (green circles),glu–arg (yellow upward triangles), and tyr–trp (reddownward triangles) systems. (B) Comparison of binding affinitiescalculated from the Cα–Cα g(r) functions from MD (x-axis) and BD (y-axis). The green, yellow, and red symbols represent theile–leu, glu–arg, and tyr–trp systems, respectively;the blue symbols represent the other 228 systems.
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fig4: Derivationof COFFDROP nonbonded potential functions using theIBI method. (A) Plot showing the error in the nonbonded g(r) functions obtained from BD simulations as afunction of IBI iteration number for the ile–leu (green circles),glu–arg (yellow upward triangles), and tyr–trp (reddownward triangles) systems. (B) Comparison of binding affinitiescalculated from the Cα–Cα g(r) functions from MD (x-axis) and BD (y-axis). The green, yellow, and red symbols represent theile–leu, glu–arg, and tyr–trp systems, respectively;the blue symbols represent the other 228 systems.

Mentions: As was the case with thebonded interactions, the IBI procedurewas used to optimize potential functions for all nonbonded interactionswith the “target” distributions to reproduce in thiscase being the pseudoatom–pseudoatom g(r) functions obtained from the CG-converted MD simulations.During the IBI procedure, the bonded potential functions that werepreviously optimized to reproduce the behavior of single amino acidswere not reoptimized; similarly, for tryptophan, the intramolecularnonbonded potential functions were not reoptimized. Shown in Figure 4A is the calculated average error in the g(r)s obtained from BD as a function ofIBI iteration for three representative interactions: ile–leu,glu–arg, and tyr–trp. In each case, the errors rapidlydecrease over the first ∼40 iterations. Following this point,the errors fluctuate in ways that depend on the particular system:the fluctuations are largest with the tyr–trp system whichis likely a consequence of it having a larger number of interactionpotentials to optimize. The IBI optimization was successful with allpairs of amino acids to the extent that binding affinities computedby integrating the Cα–Cα g(r)s obtained from BD simulations of each system were inexcellent agreement with those obtained from MD (Figure 4B); all other pseudoatom–pseudoatom g(r)s were reproduced with similar accuracy.


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)

Derivationof COFFDROP nonbonded potential functions using theIBI method. (A) Plot showing the error in the nonbonded g(r) functions obtained from BD simulations as afunction of IBI iteration number for the ile–leu (green circles),glu–arg (yellow upward triangles), and tyr–trp (reddownward triangles) systems. (B) Comparison of binding affinitiescalculated from the Cα–Cα g(r) functions from MD (x-axis) and BD (y-axis). The green, yellow, and red symbols represent theile–leu, glu–arg, and tyr–trp systems, respectively;the blue symbols represent the other 228 systems.
© Copyright Policy
Related In: Results  -  Collection

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

fig4: Derivationof COFFDROP nonbonded potential functions using theIBI method. (A) Plot showing the error in the nonbonded g(r) functions obtained from BD simulations as afunction of IBI iteration number for the ile–leu (green circles),glu–arg (yellow upward triangles), and tyr–trp (reddownward triangles) systems. (B) Comparison of binding affinitiescalculated from the Cα–Cα g(r) functions from MD (x-axis) and BD (y-axis). The green, yellow, and red symbols represent theile–leu, glu–arg, and tyr–trp systems, respectively;the blue symbols represent the other 228 systems.
Mentions: As was the case with thebonded interactions, the IBI procedurewas used to optimize potential functions for all nonbonded interactionswith the “target” distributions to reproduce in thiscase being the pseudoatom–pseudoatom g(r) functions obtained from the CG-converted MD simulations.During the IBI procedure, the bonded potential functions that werepreviously optimized to reproduce the behavior of single amino acidswere not reoptimized; similarly, for tryptophan, the intramolecularnonbonded potential functions were not reoptimized. Shown in Figure 4A is the calculated average error in the g(r)s obtained from BD as a function ofIBI iteration for three representative interactions: ile–leu,glu–arg, and tyr–trp. In each case, the errors rapidlydecrease over the first ∼40 iterations. Following this point,the errors fluctuate in ways that depend on the particular system:the fluctuations are largest with the tyr–trp system whichis likely a consequence of it having a larger number of interactionpotentials to optimize. The IBI optimization was successful with allpairs of amino acids to the extent that binding affinities computedby integrating the Cα–Cα g(r)s obtained from BD simulations of each system were inexcellent agreement with those obtained from MD (Figure 4B); all other pseudoatom–pseudoatom g(r)s were reproduced with similar accuracy.

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