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Conformational Ensembles from Experimental Data
and Computer Simulations
Poster Abstracts
79
44-POS
Board 4
The RigiFlex Approach to Modelling Structure Ensembles with Restraints from Different
Techniques
Gunnar Jeschke
.
ETH Zurich, Zurich, Switzerland.
The objective of this study is the development of a modelling approach for proteins and protein-
RNA complexes that consist of rigid domains with separately determined structure and flexible
linkers. The ensemble shall not depend on the quality of a molecular force field, but shall rather
include uncertainty from lack of experimental restraints as well as from disorder of flexible chain
sections and disorder in the rigid-domain arrangement. Such an ensemble can inform on potential
further experiments that can distinguish between individual conformations or rigid-domain
configurations.
The rigid-body problem is solved first by defining three reference points per rigid domain.
Distance distribution measurements between such reference points can overdetermine this
problem and provide information on domain arrangement disorder via the distribution width. The
solution space of reference polyhedra is efficiently sampled by distance matrix geometry. Since
the rigid bodies are chiral, their position and orientation is uniquely defined by the three
reference points. Any further restraints, such as clash avoidance, maximum length of the flexible
linkers, auxiliary distance restraints, and small-angle x-ray or neutron scattering data can be used
to prune the initial ensemble. The flexible linker ensembles can then be modelled individually by
an approach that we introduced previously for peptide chains and that can take into account
further restraints.
RigiFlex was applied to a preliminary experimental restraint set for the complex of the human
polypyrimidine tract binding protein with a virus internal entry site RNA. We found that the
RNA linkers, but not the peptide linkers restrain the structure and that small-angle neutron
scattering data are valuable already at a stage where the number of distance distribution restraints
is clearly insufficient.