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Tunable Coarse Graining for Monte Carlo Simulations of Proteins via Smoothed Energy Tables: Direct and Exchange Simulations.

Spiriti J, Zuckerman DM - J Chem Theory Comput (2014)

Bottom Line: For a greater amount of smoothing, multiple folding-unfolding transitions of the peptide were observed, along with a factor of 10-100 improvement in sampling per unit computation time, although the time spent in the unfolded state was increased compared with less smoothed simulations.Chem.Theory Comput.2006, 2, 656-666).

View Article: PubMed Central - PubMed

Affiliation: Department of Computational and Systems Biology, University of Pittsburgh , Pittsburgh, Pennsylvania 15213, United States.

ABSTRACT
Many commonly used coarse-grained models for proteins are based on simplified interaction sites and consequently may suffer from significant limitations, such as the inability to properly model protein secondary structure without the addition of restraints. Recent work on a benzene fluid (Lettieri S.; Zuckerman D. M.J. Comput. Chem.2012, 33, 268-275) suggested an alternative strategy of tabulating and smoothing fully atomistic orientation-dependent interactions among rigid molecules or fragments. Here we report our initial efforts to apply this approach to the polar and covalent interactions intrinsic to polypeptides. We divide proteins into nearly rigid fragments, construct distance and orientation-dependent tables of the atomistic interaction energies between those fragments, and apply potential energy smoothing techniques to those tables. The amount of smoothing can be adjusted to give coarse-grained models that range from the underlying atomistic force field all the way to a bead-like coarse-grained model. For a moderate amount of smoothing, the method is able to preserve about 70-90% of the α-helical structure while providing a factor of 3-10 improvement in sampling per unit computation time (depending on how sampling is measured). For a greater amount of smoothing, multiple folding-unfolding transitions of the peptide were observed, along with a factor of 10-100 improvement in sampling per unit computation time, although the time spent in the unfolded state was increased compared with less smoothed simulations. For a β hairpin, secondary structure is also preserved, albeit for a narrower range of the smoothing parameter and, consequently, for a more modest improvement in sampling. We have also applied the new method in a "resolution exchange" setting, in which each replica runs a Monte Carlo simulation with a different degree of smoothing. We obtain exchange rates that compare favorably to our previous efforts at resolution exchange (Lyman E.; Zuckerman D. M.J. Chem. Theory Comput.2006, 2, 656-666).

No MeSH data available.


Related in: MedlinePlus

Fragmentation scheme for the 20 amino acids, including three tautomersof histidine. The fragments are shown as colored rounded rectanglesunderneath the atoms assigned to each fragment. The colors serve todistinguish fragments within each residue but do not correspond directlyto fragment types. The division of the peptide backbone into fragmentsis shown for glycine, alanine, and proline. For the other amino acids,the division is the same as that for alanine. A detailed list of thefragment types and the atoms included in each is given in Table S1in the Supporting Information.
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fig1: Fragmentation scheme for the 20 amino acids, including three tautomersof histidine. The fragments are shown as colored rounded rectanglesunderneath the atoms assigned to each fragment. The colors serve todistinguish fragments within each residue but do not correspond directlyto fragment types. The division of the peptide backbone into fragmentsis shown for glycine, alanine, and proline. For the other amino acids,the division is the same as that for alanine. A detailed list of thefragment types and the atoms included in each is given in Table S1in the Supporting Information.

Mentions: The 20 aminoacids that generally make up proteins were divided into fragmentsaccording to the scheme shown in Figure 1,in which united-atom representations of the 20 amino acids out ofwhich proteins are made are divided into 32 possible types of fragments.(A detailed list of the fragment types and their uses in representingthe amino acids is shown in Table S1 in the SupportingInformation.) Each of these fragments is approximately rigidin that it contains no rotatable bonds among its heavy atoms. A referencegeometry for each of the 32 fragment types was constructed by energy-minimizingone of the amino acids containing the fragment in vacuum, then orientingthe fragment so that the principal moments of inertia aligned withthe coordinate axes. The configuration space sampled in our modelis then represented by the position ri of the center of mass and the orientation relative to thisreference geometry (expressed as a quaternion qi(51−53)) for each fragment i. Since mostpeptide bonds are in the trans configuration, thereference geometries for peptide bond fragments have this configurationas well.


Tunable Coarse Graining for Monte Carlo Simulations of Proteins via Smoothed Energy Tables: Direct and Exchange Simulations.

Spiriti J, Zuckerman DM - J Chem Theory Comput (2014)

Fragmentation scheme for the 20 amino acids, including three tautomersof histidine. The fragments are shown as colored rounded rectanglesunderneath the atoms assigned to each fragment. The colors serve todistinguish fragments within each residue but do not correspond directlyto fragment types. The division of the peptide backbone into fragmentsis shown for glycine, alanine, and proline. For the other amino acids,the division is the same as that for alanine. A detailed list of thefragment types and the atoms included in each is given in Table S1in the Supporting Information.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230378&req=5

fig1: Fragmentation scheme for the 20 amino acids, including three tautomersof histidine. The fragments are shown as colored rounded rectanglesunderneath the atoms assigned to each fragment. The colors serve todistinguish fragments within each residue but do not correspond directlyto fragment types. The division of the peptide backbone into fragmentsis shown for glycine, alanine, and proline. For the other amino acids,the division is the same as that for alanine. A detailed list of thefragment types and the atoms included in each is given in Table S1in the Supporting Information.
Mentions: The 20 aminoacids that generally make up proteins were divided into fragmentsaccording to the scheme shown in Figure 1,in which united-atom representations of the 20 amino acids out ofwhich proteins are made are divided into 32 possible types of fragments.(A detailed list of the fragment types and their uses in representingthe amino acids is shown in Table S1 in the SupportingInformation.) Each of these fragments is approximately rigidin that it contains no rotatable bonds among its heavy atoms. A referencegeometry for each of the 32 fragment types was constructed by energy-minimizingone of the amino acids containing the fragment in vacuum, then orientingthe fragment so that the principal moments of inertia aligned withthe coordinate axes. The configuration space sampled in our modelis then represented by the position ri of the center of mass and the orientation relative to thisreference geometry (expressed as a quaternion qi(51−53)) for each fragment i. Since mostpeptide bonds are in the trans configuration, thereference geometries for peptide bond fragments have this configurationas well.

Bottom Line: For a greater amount of smoothing, multiple folding-unfolding transitions of the peptide were observed, along with a factor of 10-100 improvement in sampling per unit computation time, although the time spent in the unfolded state was increased compared with less smoothed simulations.Chem.Theory Comput.2006, 2, 656-666).

View Article: PubMed Central - PubMed

Affiliation: Department of Computational and Systems Biology, University of Pittsburgh , Pittsburgh, Pennsylvania 15213, United States.

ABSTRACT
Many commonly used coarse-grained models for proteins are based on simplified interaction sites and consequently may suffer from significant limitations, such as the inability to properly model protein secondary structure without the addition of restraints. Recent work on a benzene fluid (Lettieri S.; Zuckerman D. M.J. Comput. Chem.2012, 33, 268-275) suggested an alternative strategy of tabulating and smoothing fully atomistic orientation-dependent interactions among rigid molecules or fragments. Here we report our initial efforts to apply this approach to the polar and covalent interactions intrinsic to polypeptides. We divide proteins into nearly rigid fragments, construct distance and orientation-dependent tables of the atomistic interaction energies between those fragments, and apply potential energy smoothing techniques to those tables. The amount of smoothing can be adjusted to give coarse-grained models that range from the underlying atomistic force field all the way to a bead-like coarse-grained model. For a moderate amount of smoothing, the method is able to preserve about 70-90% of the α-helical structure while providing a factor of 3-10 improvement in sampling per unit computation time (depending on how sampling is measured). For a greater amount of smoothing, multiple folding-unfolding transitions of the peptide were observed, along with a factor of 10-100 improvement in sampling per unit computation time, although the time spent in the unfolded state was increased compared with less smoothed simulations. For a β hairpin, secondary structure is also preserved, albeit for a narrower range of the smoothing parameter and, consequently, for a more modest improvement in sampling. We have also applied the new method in a "resolution exchange" setting, in which each replica runs a Monte Carlo simulation with a different degree of smoothing. We obtain exchange rates that compare favorably to our previous efforts at resolution exchange (Lyman E.; Zuckerman D. M.J. Chem. Theory Comput.2006, 2, 656-666).

No MeSH data available.


Related in: MedlinePlus