title: Benchmarking predictions of allostery in liver pyruvate kinase in CAGI4.
abstract: The Critical Assessment of Genome Interpretation (CAGI) is a global community experiment to objectively assess computational methods for predicting phenotypic impacts of genomic variation. One of the 2015-2016 competitions focused on predicting the influence of mutations on the allosteric regulation of human liver pyruvate kinase. More than 30 different researchers accessed the challenge data. However, only four groups accepted the challenge. Features used for predictions ranged from evolutionary constraints, mutant site locations relative to active and effector binding sites, and computational docking outputs. Despite the range of expertise and strategies used by predictors, the best predictions were marginally greater than random for modified allostery resulting from mutations. In contrast, several groups successfully predicted which mutations severely reduced enzymatic activity. Nonetheless, poor predictions of allostery stands in stark contrast to the impression left by more than 700 PubMed entries identified using the identifiers "computational + allosteric." This contrast highlights a specialized need for new computational tools and utilization of benchmarks that focus on allosteric regulation.
authors.affiliation: Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Qifang
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Qingling
authors.initials: Q
authors.lastname: Tang
authors.affiliation: Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Katsonis
authors.affiliation: Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lichtarge
authors.affiliation: Department of Computer Science, University College London, London, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Jones
authors.affiliation: Biocomputing Group, CIG/Interdepartmental Center «Luigi Galvani» for Integrated Studies of Bioinformatics, Biophysics and Biocomplexity, University of Bologna, Bologna, Italy.
authors.forename: Samuele
authors.initials: S
authors.lastname: Bovo
authors.affiliation: Biocomputing Group, CIG/Interdepartmental Center «Luigi Galvani» for Integrated Studies of Bioinformatics, Biophysics and Biocomplexity, University of Bologna, Bologna, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Babbi
authors.affiliation: Biocomputing Group, CIG/Interdepartmental Center «Luigi Galvani» for Integrated Studies of Bioinformatics, Biophysics and Biocomplexity, University of Bologna, Bologna, Italy.
authors.forename: Pier L
authors.initials: PL
authors.lastname: Martelli
authors.affiliation: Biocomputing Group, CIG/Interdepartmental Center «Luigi Galvani» for Integrated Studies of Bioinformatics, Biophysics and Biocomplexity, University of Bologna, Bologna, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Casadio
authors.affiliation: Department of Chemistry, Seoul National University, Seoul, Republic of Korea.
authors.forename: Gyu Rie
authors.initials: GR
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Seoul National University, Seoul, Republic of Korea.
authors.forename: Chaok
authors.initials: C
authors.lastname: Seok
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Aron W
authors.initials: AW
authors.lastname: Fenton
authors.affiliation: Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Roland L
authors.initials: RL
authors.lastname: Dunbrack
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D019985:Benchmarking / Q000379:methods*; D019295:Computational Biology / Q000379:methods; D030541:Databases, Genetic; D005635:Fructosediphosphates / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011770:Pyruvate Kinase / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
chemical_list: D005635:Fructosediphosphates; D011770:Pyruvate Kinase; C029063:fructose-1,6-diphosphate
keywords: CAGI experiment; allosteric effect; liver pyruvate kinase; missense mutation