defining an essence of structure determining residue contacts in proteins定义一个结构的本质决定残留蛋白质接触.pdfVIP

Defining an Essence of Structure Determining Residue Contacts in Proteins R. Sathyapriya, Jose M. Duarte, Henning Stehr, Ioannis Filippis, Michael Lappe* Structural Genomics/Bioinformatics Group, Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics, Berlin, Germany Abstract The network of native non-covalent residue contacts determines the three-dimensional structure of a protein. However, not all contacts are of equal structural significance, and little knowledge exists about a minimal, yet sufficient, subset required to define the global features of a protein. Characterisation of this ‘‘structural essence’’ has remained elusive so far: no algorithmic strategy has been devised to-date that could outperform a random selection in terms of 3D reconstruction accuracy (measured as the Ca RMSD). It is not only of theoretical interest (i.e., for design of advanced statistical potentials) to identify the number and nature of essential native contacts—such a subset of spatial constraints is very useful in a number of novel experimental methods (like EPR) which rely heavily on constraint-based protein modelling. To derive accurate three-dimensional models from distance constraints, we implemented a reconstruction pipeline using distance geometry. We selected a test-set of 12 protein structures from the four major SCOP fold classes and performed our reconstruction analysis. As a reference set, series of random subsets (ranging from 10% to 90% of native contacts) are generated for each protein, and the reconstruction accuracy is computed for each subset. We have developed a rational strategy, termed ‘‘cone-peeling’’ that combines sequence features and network descriptors to select minimal subsets that outperform the