1,112 research outputs found
Computational Protein Design Using AND/OR Branch-and-Bound Search
The computation of the global minimum energy conformation (GMEC) is an
important and challenging topic in structure-based computational protein
design. In this paper, we propose a new protein design algorithm based on the
AND/OR branch-and-bound (AOBB) search, which is a variant of the traditional
branch-and-bound search algorithm, to solve this combinatorial optimization
problem. By integrating with a powerful heuristic function, AOBB is able to
fully exploit the graph structure of the underlying residue interaction network
of a backbone template to significantly accelerate the design process. Tests on
real protein data show that our new protein design algorithm is able to solve
many prob- lems that were previously unsolvable by the traditional exact search
algorithms, and for the problems that can be solved with traditional provable
algorithms, our new method can provide a large speedup by several orders of
magnitude while still guaranteeing to find the global minimum energy
conformation (GMEC) solution.Comment: RECOMB 201
Computational methods for finding long simple cycles in complex networks
© 2017 Elsevier B.V. Detection of long simple cycles in real-world complex networks finds many applications in layout algorithms, information flow modelling, as well as in bioinformatics. In this paper, we propose two computational methods for finding long cycles in real-world networks. The first method is an exact approach based on our own integer linear programming formulation of the problem and a data mining pipeline. This pipeline ensures that the problem is solved as a sequence of integer linear programs. The second method is a multi-start local search heuristic, which combines an initial construction of a long cycle using depth-first search with four different perturbation operators. Our experimental results are presented for social network samples, graphs studied in the network science field, graphs from DIMACS series, and protein-protein interaction networks. These results show that our formulation leads to a significantly more efficient exact approach to solve the problem than a previous formulation. For 14 out of 22 networks, we have found the optimal solutions. The potential of heuristics in this problem is also demonstrated, especially in the context of large-scale problem instances
Computational Design of a PDZ Domain Peptide Inhibitor that Rescues CFTR Activity
The cystic fibrosis transmembrane conductance regulator (CFTR) is an epithelial chloride channel mutated in patients with cystic fibrosis (CF). The most prevalent CFTR mutation, ΔF508, blocks folding in the endoplasmic reticulum. Recent work has shown that some ΔF508-CFTR channel activity can be recovered by pharmaceutical modulators (“potentiators” and “correctors”), but ΔF508-CFTR can still be rapidly degraded via a lysosomal pathway involving the CFTR-associated ligand (CAL), which binds CFTR via a PDZ interaction domain. We present a study that goes from theory, to new structure-based computational design algorithms, to computational predictions, to biochemical testing and ultimately to epithelial-cell validation of novel, effective CAL PDZ inhibitors (called “stabilizers”) that rescue ΔF508-CFTR activity. To design the “stabilizers”, we extended our structural ensemble-based computational protein redesign algorithm to encompass protein-protein and protein-peptide interactions. The computational predictions achieved high accuracy: all of the top-predicted peptide inhibitors bound well to CAL. Furthermore, when compared to state-of-the-art CAL inhibitors, our design methodology achieved higher affinity and increased binding efficiency. The designed inhibitor with the highest affinity for CAL (kCAL01) binds six-fold more tightly than the previous best hexamer (iCAL35), and 170-fold more tightly than the CFTR C-terminus. We show that kCAL01 has physiological activity and can rescue chloride efflux in CF patient-derived airway epithelial cells. Since stabilizers address a different cellular CF defect from potentiators and correctors, our inhibitors provide an additional therapeutic pathway that can be used in conjunction with current methods
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