Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data and Computer Simulations

Poster Abstracts

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.

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