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Nucleic Acids Res. 2014 Jan;42(1):97-108. doi: 10.1093/nar/gkt890. Epub 2013 Oct 3.

De novo prediction of DNA-binding specificities for Cys2His2 zinc finger proteins.

Author information

1
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton NJ 08544, USA and Department of Computer Science, Princeton University, Princeton NJ 08544, USA.

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.

PMID:
24097433
PMCID:
PMC3874201
DOI:
10.1093/nar/gkt890
[Indexed for MEDLINE]
Free PMC Article

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