Biomedical Engineering Reference
In-Depth Information
employ sophisticated search methods. Typical NMR restraints and their
instructiveness and resolution are discussed in Section 4.3. When only little
guidance is available, extensive sampling is required to identify the relatively
small volume in conformational space that is the low energy region around the
native structure. Solving this sampling problem is the main challenge for
structure determination with guidance-sparse restraints, and novel suitable
optimisation methods are discussed in Section 4.4.
4.2
Force-Fields
4.2.1 Introduction to Force-Fields
In the context of structure calculation a force-field refers to the functional form
and parameter sets used to compute the potential energy V(x) of the structure
in conformation x. Generally the potential energy can be separated into
bonded and non-bonded contributions, V(x) 5 V
bonded
(x) + V
non-bonded
(x)
with bonded terms comprising bond lengths, angles, chiralities, planarities and
dihedrals, and non-bonded terms comprising van der Waals interactions,
hydrogen bonds, and charged interactions.
For simplicity of the non-covalent interactions, force-fields rely mostly on
pairwise terms, but multi-body terms have been explored, too.
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To introduce
multi-body effects without abandoning the simpler pairwise formulation,some
force-fields introduce context-dependent potentials. For instance, the well depth
of a hydrogen bonding potential depends on the number of neighbours at the
donor and acceptor atoms in the ROSETTA all-atom force-field (RAAFF).
4.2.2 Hybrid Molecular Mechanics Force-Fields
The commonly applied force-fields for NMR structure calculations in the
software packages XPLOR or CNS are derived from the CHARMM,
AMBER or OPLS all-atom force-fields. These force-fields are originally
parameterised for classical molecular dynamics (MD) simulations with the aim
to produce correct thermodynamics and kinetics in temperature-coupled MD
simulations. In order to produce idealised average local geometry that is
consistent and in balance with the experimental data, stiffer parameters are
required which led to hybrid potentials using covalent parameters from
crystallographic force-fields.
31,34
Whereas great care was put into the
development and validation of well-balanced parameter sets for MD
simulation, this has not been necessary in the context of structure calculations
with dense restraint sets, because the data is supposed to dominate the results.
4.2.3 The ROSETTA All-Atom Force-Field
The ROSETTA all-atom force-field (RAAFF) is a dedicated structure-
prediction force-field and has been successful in both structure prediction and
