Protein fragment reconstruction using various modeling techniques

Abstract

SummaryRecently developed reduced models of proteins with knowledge-based force fields have been applied to a specific case of comparative modeling. From twenty high resolution protein structures of various structural classes, significant fragments of their chains have been removed and treated as unknown. The remaining portions of the structures were treated as fixed -i.e., as templates with an exact alignment. Then, the missed fragments were reconstructed using several modeling tools. These included three reduced types of protein models: the lattice SICHO (Side Chain Only) model, the lattice CABS (Cα + Cβ + Side group) model and an off-lattice model similar to the CABS model and called REFINER. The obtained reduced models were compared with more standard comparative modeling tools such as MODELLER and the SWISS-MODEL server. The reduced model results are qualitatively better for the higher resolution lattice models, clearly suggesting that these are now mature, competitive and complementary (in the range of sparse alignments) to the classical tools of comparative modeling. Comparison between the various reduced models strongly suggests that the essential ingredient for the sucessful and accurate modeling of protein structures is not the representation of conformational space (lattice, off-lattice, all-atom) but, rather, the specificity of the force fields used and, perhaps, the sampling techniques employed. These conclusions are encouraging for the future application of the fast reduced models in comparative modeling on a genomic scale.

Structure and intrinsic disorder of the proteins of theTrypanosoma brucei editosome

“…Representative members of the largest clusters were selected for further analysis. Finally, for regions that remained poorly scored, local refinement with restraints on the predicted secondary structure was attempted using the REFINER program [34].…”

Theoretical model of prion propagation: A misfolded protein induces misfolding

“…In particular, we have used the replica exchange Monte Carlo method, in which many Monte Carlo simulations (for a series of different temperatures) are simultaneously under way and the generalized Metropolis criterion enables one to accept conformations also computed for different temperatures. The details of this modeling tool can be found in our recent publications (26,27).…”

“…Protein is represented as a chain of C␣ atoms in continuous space (26,27). The idea of the reduced representation of polypeptide conformational space in the REFINER model is illustrated in Fig.…”

“…The details of the design and derivation of the potentials are very similar to the design of force field for analogous high-resolution lattice model (29,32). The REFINER modeling tool had been previously tested during the CASP5 experiment (26) and in a benchmark of de novo prediction of protein fragments (27), which demonstrated better performance (accuracy and reproducibility) than was possible with standard molecular modeling tools. During the last round of the communitywide protein structure prediction experiment (CASP6) the REFINER model and its force field produced several very good predictions, especially in the new fold category.…”

“…Then, a long series of simulations enabled us to select a single sequence that exhibited strong autocatalytic effect, leading to spontaneous formation of the amyloid protofibrils, provided the process was initiated by freezing one of the molecules in the ␤-type metastable conformation. Simulations were performed by using a high-resolution reduced representation of protein conformational space, the REFINER model (26,27), and replica exchange Monte Carlo method (28) as an effective sampling scheme. The model uses united atom representation and continuous space conformational updating.…”