Taking the step from experimental NMR data
to a three
dimensional protein structure should be straightforward,
given the countless years of expertise accumulated in the many programs
developed for this purpose. In practice however, it turns out that the
path is cluttered with potential pitfalls, some of which may even
redirect the search to the wrong answer.
The key problem is that experimental NMR
data provide only part of the
answer - the rest has to be filled in by the software, relying on a
priori knowledge about the look of a protein. This knowledge is
both essential and dangerous: essential because it provides the only
way to extract a concise 3D structure from the often noisy and
contradictory raw data, and dangerous because it may suppress novel
structural features that have not been seen before.
All the crucial knowledge is contained in
the force field - which is also the main distinguishing feature
between different programs. Ever since the release of YASARA's first
own force field in 1997, we have focused on getting the a priori
right and improving the force
field accuracy. Recent advances included the
self-parameterizing NOVA force field in 2002, which derived its own
parameters while energy minimizing protein structures, and the
extension of this approach to entire high resolution protein crystals
in 2004, leading to the YAMBER force fields. In 2006, the YASARA
force field incorporated knowledge-based torsion potentials in a way
that increased the accuracy without preventing the protein from
adapting novel or unusual conformations (last image on the right).
While YASARA's optimized force fields
form the core of the NMR structure determination module, the following
additional features are noteworthy:
- Fully automatic: Requires a FASTA sequence file, a
restraint file and five mouse clicks to generate the result. Force
field parameters for unusual amino acids are also derived automatically from semi-empirical
- YASARA reads distance- and dihedral angle restraints
in standard X-PLOR format and provides the same restraining functions
(biharmonic, square well, soft-square) and averaging methods (R-3,
R-6, sum, center) as X-PLOR, so that you can easily use
- Real-time structure generation: watch the protein
fold on screen, show the NOEs, differentiate between fulfilled and
violated ones, identify regions of conformational stress and potential
- The entire structure determination protocol has been
implemented in YASARA's trivial Yanaconda macro
language, which makes
it easy to adapt everything to very specific requirements.
The NMR structure determination module is
available as an add-on to YASARA
Structure. A list of structures solved with YASARA can be found in the publication list, if you search for "PDB ID".
R E F E R E N C E S
 Traditional biomolecular structure determination by NMR
spectroscopy allows for major errors
Nabuurs SB, Spronk CA, Vuister GW, Vriend G (2006) PLoS
Comput Biol. 2(2)
 GTP-Ras Disrupts the
Intramolecular Complex of C1 and RA Domains of Nore1
Harjes E, Harjes S, Wohlgemuth S, Muller KH, Krieger E, Herrmann C,
Bayer P (2006) Structure 14, 881-888.
 Increasing the precision of
comparative models with YASARA NOVA - a self-parameterizing force field
Krieger E, Koraimann G, Vriend G (2002) Proteins 47,
 Making optimal use of empirical
energy functions: Force-field parameterization in crystal space
Krieger E, Darden T, Nabuurs SB, Finkelstein A, Vriend G (2004) Proteins 57, 678-683
of the Tyrosine-sulfated C5a Receptor N Terminus in Complex with
Chemotaxis Inhibitory Protein of Staphylococcus aureus
Ippel JH, de Haas CJ, Bunschoten A, van Strijp JA, Kruijtzer JA, Liskamp RM, Kemmink J (2009) J Biol Chem 284, 12363-72
 NMR structure of the human prion protein with the pathological Q212P mutation reveals unique structural features
Ilc G, Giachin G, Jaremko M, Jaremko L, Benetti F, Plavec J, Zhukov I, Legname G (2010) PLoS One 5, e11715
|Figure 1: An NMR structure solved
with YASARA by Elena Harjes et al.
: The C1 domain of mNore1, a novel Ras effector. The cover
of Structure Vol. 14/5 has also been created with YASARA and shows
the C1 domain in the foreground, after it has lost the intraaction with
the RA domain (yellow), which is now bound to a
Ras protein (orange) attached to the membrane surface in the
|Figure 2: The C1 domain of mNore1 as
determined by Elena Harjes et al.
. Click here to download the top five
ensemble structures, with no NOE violations > 0.5 Å and no
torsion violations > 5°.
The structure of tyrosine-sulfated C5a receptor (N-terminus) with
bound chemotaxis inhibitory protein (shown in grey) from
S. aureus. Ippel et al. used YASARA to dock the two proteins based on NOE restraints, PDB file 2K3U. Other examples (not shown) include a human prion protein mutant.
|Figure 4: Knowledge based torsion
potentials helping to increase force field accuracy. Arrows indicate
the current torsion angles in one or two dimensions.