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Orthogonal γPNA Dimerization Domains Empower DNA Binders with Cooperativity and Versatility Mimicking that of Transcription Factor Pairs
Author(s) -
Yu Zutao,
Hsieh WeiChe,
Asamitsu Sefan,
Hashiya Kaori,
Bando Toshikazu,
Ly Danith H.,
Sugiyama Hiroshi
Publication year - 2018
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201801961
Subject(s) - cooperativity , dna , transcription factor , computational biology , cooperative binding , genetics , chemistry , biophysics , microbiology and biotechnology , biology , gene , binding site
Synthetic molecules capable of DNA binding and mimicking cooperation of transcription factor (TF) pairs have long been considered a promising tool for manipulating gene expression. Our previously reported Pip‐HoGu system, a programmable DNA binder pyrrole‐imidazole polyamides (PIPs) conjugated to host–guest moiety, defined a general framework for mimicking cooperative TF pair‐DNA interactions. Here, we supplanted the cooperation modules with left‐handed (LH) γPNA modules: i.e., PIP s conjugated with n ucleic a cid‐based c ooperation s ystem (Pip‐NaCo). LH γPNA was chosen because of its bioorthogonality, sequence‐specific interaction, and high binding affinity toward the partner strand. From the results of the Pip‐NaCo system, cooperativity is highly comparable to the natural TF pair‐DNA system, with a minimum energetics of cooperation of −3.27 kcal mol −1 . Moreover, through changing the linker conjugation site, binding mode, and the length of γPNAs sequence, the cooperative energetics of Pip‐NaCo can be tuned independently and rationally. The current Pip‐NaCo platform might also have the potential for precise manipulation of biological processes through the construction of triple to multiple heterobinding systems.