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Hum Mutat. 2017 Sep;38(9):1123-1131. doi: 10.1002/humu.23222. Epub 2017 May 2.

Benchmarking predictions of allostery in liver pyruvate kinase in CAGI4.

Author information

1
Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
2
Department of Biochemistry and Molecular Biology, The University of Kansas Medical Center, Kansas City, Kansas.
3
Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas.
4
Department of Computer Science, University College London, London, United Kingdom.
5
Biocomputing Group, CIG/Interdepartmental Center «Luigi Galvani» for Integrated Studies of Bioinformatics, Biophysics and Biocomplexity, University of Bologna, Bologna, Italy.
6
Department of Chemistry, Seoul National University, Seoul, Republic of Korea.

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.

KEYWORDS:

CAGI experiment; allosteric effect; liver pyruvate kinase; missense mutation

PMID:
28370845
PMCID:
PMC5561472
DOI:
10.1002/humu.23222
[Indexed for MEDLINE]
Free PMC Article

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