De novo prediction of DNA-binding specificities for Cys2His 2 zinc finger proteins

Anton V. Persikov, Mona Singh

Research output: Contribution to journalArticle

80 Scopus citations

Abstract

Proteins with sequence-specific DNA binding function are important for a wide range of biological activities. De novo prediction of their DNA-binding specificities from sequence alone would be a great aid in inferring cellular networks. Here we introduce a method for predicting DNA-binding specificities for Cys2His2 zinc fingers (C2H2-ZFs), the largest family of DNA-binding proteins in metazoans. We develop a general approach, based on empirical calculations of pairwise amino acid-nucleotide interaction energies, for predicting position weight matrices (PWMs) representing DNA-binding specificities for C2H2-ZF proteins. We predict DNA-binding specificities on a per-finger basis and merge predictions for C2H2-ZF domains that are arrayed within sequences. We test our approach on a diverse set of natural C2H2-ZF proteins with known binding specificities and demonstrate that for >85% of the proteins, their predicted PWMs are accurate in 50% of their nucleotide positions. For proteins with several zinc finger isoforms, we show via case studies that this level of accuracy enables us to match isoforms with their known DNA-binding specificities. A web server for predicting a PWM given a protein containing C2H2-ZF domains is available online at http://zf.princeton. edu and can be used to aid in protein engineering applications and in genome-wide searches for transcription factor targets.

Original languageEnglish (US)
Pages (from-to)97-108
Number of pages12
JournalNucleic acids research
Volume42
Issue number1
DOIs
StatePublished - Jan 7 2014

All Science Journal Classification (ASJC) codes

  • Genetics

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