Progress and challenges in high-resolution refinement of protein structure models.

@article{citeulike:600425, abstract = {Achieving atomic level accuracy in de novo structure prediction presents a formidable challenge even in the context of protein models with correct topologies. High-resolution refinement is a fundamental test of force field accuracy and sampling methodology, and its limited success in both comparative modeling and de novo prediction contexts highlights the limitations of current approaches. We constructed four tests to identify bottlenecks in our current approach and to guide progress in this challenging area. The first three tests showed that idealized native structures are stable under our refinement simulation conditions and that the refinement protocol can significantly decrease the root mean square deviation (RMSD) of perturbed native structures. In the fourth test we applied the refinement protocol to de novo models and showed that accurate models could be identified based on their energies, and in several cases many of the buried side chains adopted native-like conformations. We also showed that the differences in backbone and side-chain conformations between the refined de novo models and the native structures are largely localized to loop regions and regions where the native structure has unusual features such as rare rotamers or atypical hydrogen bonding between beta-strands. The refined de novo models typically have higher energies than refined idealized native structures, indicating that sampling of local backbone conformations and side-chain packing arrangements in a condensed state is a primary obstacle.}, address = {Department of Biochemistry, University of Washington Health Sciences, Seattle, Washington 98195-7350, USA.}, author = {Misura, K. M. and Baker, D. }, citeulike-article-id = {600425}, doi = {10.1002/prot.20376}, issn = {1097-0134}, journal = {Proteins}, keywords = {pfc3, structural\_modeling}, month = {April}, number = {1}, pages = {15--29}, posted-at = {2008-04-16 15:51:01}, priority = {2}, title = {Progress and challenges in high-resolution refinement of protein structure models.}, url = {http://dx.doi.org/10.1002/prot.20376}, volume = {59}, year = {2005} }

TY - JOUR ID - citeulike:600425 L3 - citeulike-article-id:600425 TI - Progress and challenges in high-resolution refinement of protein structure models. JF - Proteins VL - 59 IS - 1 SP - 15 EP - 29 AD - Department of Biochemistry, University of Washington Health Sciences, Seattle, Washington 98195-7350, USA. SN - 1097-0134 N2 - Achieving atomic level accuracy in de novo structure prediction presents a formidable challenge even in the context of protein models with correct topologies. High-resolution refinement is a fundamental test of force field accuracy and sampling methodology, and its limited success in both comparative modeling and de novo prediction contexts highlights the limitations of current approaches. We constructed four tests to identify bottlenecks in our current approach and to guide progress in this challenging area. The first three tests showed that idealized native structures are stable under our refinement simulation conditions and that the refinement protocol can significantly decrease the root mean square deviation (RMSD) of perturbed native structures. In the fourth test we applied the refinement protocol to de novo models and showed that accurate models could be identified based on their energies, and in several cases many of the buried side chains adopted native-like conformations. We also showed that the differences in backbone and side-chain conformations between the refined de novo models and the native structures are largely localized to loop regions and regions where the native structure has unusual features such as rare rotamers or atypical hydrogen bonding between beta-strands. The refined de novo models typically have higher energies than refined idealized native structures, indicating that sampling of local backbone conformations and side-chain packing arrangements in a condensed state is a primary obstacle. KW - pfc3 KW - structural_modeling AU - Misura, KM AU - Baker, D PY - 2005/04/01/ UR - http://dx.doi.org/10.1002/prot.20376 ER -