title: comets (Constrained Optimization of Multistate Energies by Tree Search): A Provable and Efficient Protein Design Algorithm to Optimize Binding Affinity and Specificity with Respect to Sequence.
abstract: Practical protein design problems require designing sequences with a combination of affinity, stability, and specificity requirements. Multistate protein design algorithms model multiple structural or binding "states" of a protein to address these requirements. comets provides a new level of versatile, efficient, and provable multistate design. It provably returns the minimum with respect to sequence of any desired linear combination of the energies of multiple protein states, subject to constraints on other linear combinations. Thus, it can target nearly any combination of affinity (to one or multiple ligands), specificity, and stability (for multiple states if needed). Empirical calculations on 52 protein design problems showed comets is far more efficient than the previous state of the art for provable multistate design (exhaustive search over sequences). comets can handle a very wide range of protein flexibility and can enumerate a gap-free list of the best constraint-satisfying sequences in order of objective function value.
authors.affiliation: 1 Department of Computer Science, Levine Science Research Center, Duke University , North Carolina.|2 Department of Biochemistry, Duke University Medical Center , Durham, North Carolina.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hallen
authors.affiliation: 1 Department of Computer Science, Levine Science Research Center, Duke University , North Carolina.|2 Department of Biochemistry, Duke University Medical Center , Durham, North Carolina.|3 Department of Chemistry, Duke University , Durham, North Carolina.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Donald
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D008958:Models, Molecular; D011485:Protein Binding; D055550:Protein Stability; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D011506:Proteins
keywords: algorithms; branch-and-bound; combinatorial optimization; drug design; protein structure