5 research outputs found
The Amber ff99 Force Field Predicts Relative Free Energy Changes for RNA Helix Formation
The ability of the Amber ff99 force field to predict
relative free
energies of RNA helix formation was investigated. The test systems
were three hexaloop RNA hairpins with identical loops and varying
stems. The potential of mean force of stretching the hairpins from
the native state to an extended conformation was calculated with umbrella
sampling. Because the hairpins have identical loop sequence, the differences
in free energy changes are only from the stem composition. The Amber
ff99 force field was able to correctly predict the order of stabilities
of the hairpins, although the magnitude of the free energy change
is larger than that determined by optical melting experiments. The
two measurements cannot be compared directly because the unfolded
state in the optical melting experiments is a random coil, while the
end state in the umbrella sampling simulations was an elongated chain.
The calculations can be compared to reference data by using a thermodynamic
cycle. By applying the thermodynamic cycle to the transitions between
the hairpins using simulations and nearest-neighbor data, agreement
was found to be within the sampling error of simulations, thus demonstrating
that ff99 force field is able to accurately predict relative free
energies of RNA helix formation
DNA Duplex Formation with a Coarse-Grained Model
A middle-resolution
coarse-grained model of DNA is proposed. The
DNA chain is built of spherical and planar rigid bodies connected
by elastic virtual bonds. The bonded part of the potential energy
function is fit to potentials of mean force of model systems. The
rigid bodies are sets of neutral, charged, and dipolar beads. Electrostatic
and van der Waals interactions are parametrized by our recently developed
procedure [Maciejczyk, M.; Spasic, A.; Liwo, A.; Scheraga, H.A. <i>J. Comp. Chem.</i> <b>2010</b>, <i>31</i>, 1644].
Interactions with the solvent and an ionic cloud are approximated
by a multipole–multipole Debye–Hückel model.
A very efficient <i>R</i>-RATTLE algorithm, for integrating
the movement of rigid bodies, is implemented. It is the first coarse-grained
model, in which both bonded and nonbonded interactions were parametrized
ab initio and which folds stable double helices from separated complementary
strands, with the final conformation close to the geometry of experimentally
determined structures
Modified Amber Force Field Correctly Models the Conformational Preference for Tandem GA pairs in RNA
Molecular mechanics with all-atom
models was used to understand
the conformational preference of tandem guanine-adenine (GA) noncanonical
pairs in RNA. These tandem GA pairs play important roles in determining
stability, flexibility, and structural dynamics of RNA tertiary structures.
Previous solution structures showed that these tandem GA pairs adopt
either imino (cis Watson–Crick/Watson–Crick A-G) or
sheared (trans Hoogsteen/sugar edge A-G) conformations depending on
the sequence and orientation of the adjacent closing base pairs. The
solution structures (GCGGACGC)<sub>2</sub> [<i>Biochemistry</i>, <b>1996</b>, <i>35</i>, 9677–9689] and (GCGGAUGC)<sub>2</sub> [<i>Biochemistry</i>, <b>2007</b>, <i>46</i>, 1511–1522] demonstrate imino and sheared conformations
for the two central GA pairs, respectively. These systems were studied
using molecular dynamics and free energy change calculations for conformational
changes, using umbrella sampling. For the structures to maintain their
native conformations during molecular dynamics simulations, a modification
to the standard Amber ff10 force field was required, which allowed
the amino group of guanine to leave the plane of the base [<i>J. Chem. Theory Comput</i>., <b>2009</b>, <i>5</i>, 2088–2100] and form out-of-plane hydrogen bonds with a cross-strand
cytosine or uracil. The requirement for this modification suggests
the importance of out-of-plane hydrogen bonds in stabilizing the native
structures. Free energy change calculations for each sequence demonstrated
the correct conformational preference when the force field modification
was used, but the extent of the preference is underestimated
Revised RNA Dihedral Parameters for the Amber Force Field Improve RNA Molecular Dynamics
The
backbone dihedral parameters of the Amber RNA force field were
improved by fitting using multiple linear regression to potential
energies determined by quantum chemistry calculations. Five backbone
and four glycosidic dihedral parameters were fit simultaneously to
reproduce the potential energies determined by a high-level density
functional theory calculation (B97D3 functional with the AUG-CC-PVTZ
basis set). Umbrella sampling was used to determine conformational
free energies along the dihedral angles, and these better agree with
the population of conformations observed in the protein data bank
for the new parameters than for the conventional parameters. Molecular
dynamics simulations performed on a set of hairpin loops, duplexes
and tetramers with the new parameter set show improved modeling for
the structures of tetramers CCCC, CAAU, and GACC, and an RNA internal
loop of noncanonical pairs, as compared to the conventional parameters.
For the tetramers, the new parameters largely avoid the incorrect
intercalated structures that dominate the conformational samples from
the conventional parameters. For the internal loop, the major conformation
solved by NMR is stable with the new parameters, but not with the
conventional parameters. The new force field performs similarly to
the conventional parameters for the UUCG and GCAA hairpin loops and
the [UÂ(UA)<sub>6</sub>A]<sub>2</sub> duplex
Revised RNA Dihedral Parameters for the Amber Force Field Improve RNA Molecular Dynamics
The
backbone dihedral parameters of the Amber RNA force field were
improved by fitting using multiple linear regression to potential
energies determined by quantum chemistry calculations. Five backbone
and four glycosidic dihedral parameters were fit simultaneously to
reproduce the potential energies determined by a high-level density
functional theory calculation (B97D3 functional with the AUG-CC-PVTZ
basis set). Umbrella sampling was used to determine conformational
free energies along the dihedral angles, and these better agree with
the population of conformations observed in the protein data bank
for the new parameters than for the conventional parameters. Molecular
dynamics simulations performed on a set of hairpin loops, duplexes
and tetramers with the new parameter set show improved modeling for
the structures of tetramers CCCC, CAAU, and GACC, and an RNA internal
loop of noncanonical pairs, as compared to the conventional parameters.
For the tetramers, the new parameters largely avoid the incorrect
intercalated structures that dominate the conformational samples from
the conventional parameters. For the internal loop, the major conformation
solved by NMR is stable with the new parameters, but not with the
conventional parameters. The new force field performs similarly to
the conventional parameters for the UUCG and GCAA hairpin loops and
the [UÂ(UA)<sub>6</sub>A]<sub>2</sub> duplex