Limits...
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

Overall speedup in sampling per unit CPUtime as a function ofthe degree of interaction smoothing (a, b) for Leu12 or (c, d) forthe GB1 hairpin relative to MC simulations without tabulation (red)or MD simulations (green). Sampling assessed based on rate of transitionsbetween (a, c) Ramachandran plot regions or (b, d) excursions to highRMSD (>2.5 Å for Leu12, > 2.0 Å for GB1 hairpin).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4230378&req=5

fig5: Overall speedup in sampling per unit CPUtime as a function ofthe degree of interaction smoothing (a, b) for Leu12 or (c, d) forthe GB1 hairpin relative to MC simulations without tabulation (red)or MD simulations (green). Sampling assessed based on rate of transitionsbetween (a, c) Ramachandran plot regions or (b, d) excursions to highRMSD (>2.5 Å for Leu12, > 2.0 Å for GB1 hairpin).

Mentions: Although the use of tablesdid not reduce the amount of time neededto calculate the energy, the smoothing procedure for the tables doesresult in a smoother free energy surface, as indicated by increasedconformational sampling in the simulations. We quantify this increasedsampling by comparing the rates of Ramachandran transitions and RMSDexcursions in smoothed versus unsmoothed simulations. For Leu12, bothof these rates increase with the angular scale of smoothing, and moderatelevels of interaction smoothing (about 30–60°) are ableto counteract this effect (Figure 5). Dependingon the amount of smoothing applied, up to a 1 order of magnitude increasein the rate of Ramachandran transitions and up to a 2 orders of magnitudeincrease in high-RMSD excursions could be obtained for both systems,relative to Monte Carlo simulations without tabulation. With moremoderate levels of interaction smoothing (about 40–50°),which do not distort the structure of the system as significantly,an approximately 2.5-fold increase in the rate of Ramachandran transitionsand a 10-fold increase in high-RMSD excursions may be possible. Forthe GB1 hairpin, the rate of Ramachandran transitions does not increasewith increasing smoothing, but the rate of RMSD excursions does. A5–10-fold increase in the rate of RMSD excursions is possiblewith moderate amounts of smoothing (about 20–30°), althougheven these appear to introduce significant deviations in the freeenergy surface as described above. The use of tables alone, withoutsmoothing, decreases both of these sampling rates compared with simulationswithout tabulation. This appears to be due to the finite resolutionof the tables, which causes discontinuous jumps in energy that increasethe roughness of the energy surface.


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)

Overall speedup in sampling per unit CPUtime as a function ofthe degree of interaction smoothing (a, b) for Leu12 or (c, d) forthe GB1 hairpin relative to MC simulations without tabulation (red)or MD simulations (green). Sampling assessed based on rate of transitionsbetween (a, c) Ramachandran plot regions or (b, d) excursions to highRMSD (>2.5 Å for Leu12, > 2.0 Å for GB1 hairpin).
© Copyright Policy
Related In: Results  -  Collection

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

fig5: Overall speedup in sampling per unit CPUtime as a function ofthe degree of interaction smoothing (a, b) for Leu12 or (c, d) forthe GB1 hairpin relative to MC simulations without tabulation (red)or MD simulations (green). Sampling assessed based on rate of transitionsbetween (a, c) Ramachandran plot regions or (b, d) excursions to highRMSD (>2.5 Å for Leu12, > 2.0 Å for GB1 hairpin).
Mentions: Although the use of tablesdid not reduce the amount of time neededto calculate the energy, the smoothing procedure for the tables doesresult in a smoother free energy surface, as indicated by increasedconformational sampling in the simulations. We quantify this increasedsampling by comparing the rates of Ramachandran transitions and RMSDexcursions in smoothed versus unsmoothed simulations. For Leu12, bothof these rates increase with the angular scale of smoothing, and moderatelevels of interaction smoothing (about 30–60°) are ableto counteract this effect (Figure 5). Dependingon the amount of smoothing applied, up to a 1 order of magnitude increasein the rate of Ramachandran transitions and up to a 2 orders of magnitudeincrease in high-RMSD excursions could be obtained for both systems,relative to Monte Carlo simulations without tabulation. With moremoderate levels of interaction smoothing (about 40–50°),which do not distort the structure of the system as significantly,an approximately 2.5-fold increase in the rate of Ramachandran transitionsand a 10-fold increase in high-RMSD excursions may be possible. Forthe GB1 hairpin, the rate of Ramachandran transitions does not increasewith increasing smoothing, but the rate of RMSD excursions does. A5–10-fold increase in the rate of RMSD excursions is possiblewith moderate amounts of smoothing (about 20–30°), althougheven these appear to introduce significant deviations in the freeenergy surface as described above. The use of tables alone, withoutsmoothing, decreases both of these sampling rates compared with simulationswithout tabulation. This appears to be due to the finite resolutionof the tables, which causes discontinuous jumps in energy that increasethe roughness of the energy surface.

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