Improved beta‐protein structure prediction by multilevel optimization of nonlocal strand pairings and local backbone conformation

Proteins with complex, nonlocal beta-sheets are challenging for de novo structure prediction, due in part to the difficulty of efficiently sampling long-range strand pairings. We present a new, multilevel approach to beta-sheet structure prediction that circumvents this difficulty by reformulating structure generation in terms of a folding tree. Nonlocal connections in this tree allow us to explicitly sample alternative beta-strand pairings while simultaneously exploring local conformational space using backbone torsion-space moves. An iterative, energy-biased resampling strategy is used to explore the space of beta-strand pairings; we expect that such a strategy will be generally useful for searching large conformational spaces with a high degree of combinatorial complexity.