本文主要研究内容
作者（2019）在《pH-Controlled DNA Molecular Switch Using Minidumbbell》一文中研究指出：DNA is an attractive biomaterial for constructing nanomachines and nanomaterials owing to their self-recognition and self-assembly properties.In addition to the well-known double helical structures,DNA molecules can also form a variety of unusual structures like hairpins,triplexes and quadruplexes.These unusual DNAs sometimes have advantages over double helical DNAs in constructing nanomachines such as enhanced thermodynamic stability and higher sensitivity to external stimuli,which made them as promising motifs in recenttwo decades.Regardless of how complicated DNA-based nanomachines are,the fundamental concept in these nanomachines is based on a proper design and usage of DNA molecular switch.Among the reported DNA molecular switches,pH-controlled systems show great potentials in drug delivery and cellular pH sensing.Up to now,most of the reported pH-controlled molecular switches used i-motif or triplex DNAs.However,owing to the relatively long sequence requirement for the formation of i-motif and triplex DNAs,an invading DNA strand needs to be added to activate the molecular switch,and thus DNA wastes will be generated into the system and a full structural conversion will usually take a relatively long time of minutes to hours.To overcome the disadvantages of DNA waste generation and slow kinetics,molecular switches using smaller-size,thermodynamically stable and pH-sensible unusual DNA structures will have the advantages of easier manipulation and faster kinetics.Recently,we discovered a new type of unusual DNA structure called the minidumbbell(MDB)which is formed by a single-strand 8-nucleotide sequence.The MDB is composed of two type II tetraloops in which the first and fourth loop residues form loop-closing base pairs,the second loop residues fold into the minor groove to form base-base stacking or mispairing interactions,and the third loop residues stack on their nearby loop-closing base pairs.In particular,the MDB formed by a sequence containing two CCTG repeats has a relatively low melting temperature(Tm)of～22℃at pH 7.0,whereas its Tm can be significantly increased to～46℃at pH 5.0 due to the formation of a three hydrogen bond hemiprotonated C+·C mispair in the minor groove.This MDB,when combined with its complementary sequence,shows instant and complete structural conversions when the pH switches between 5.0 and 7.0 without using an invading DNA strand,serving as a simple and efficient pH-controlled molecular switch.In order to allow the incorporation of fluorophores to the two termini of the MDB,we aim to design a thermodynamically more stable MDB structure in this study.Through a rational design by introducing hydrophobic interactions to the MDB formed by the sequence containing two CCTG repeats at pH 5.0,we obtained an MDB structure with a record-high Tm of～62℃.Furthermore,this MDB was found to exist stably in the presence of 5’and 3’-overhanging residues,revealing its capability of being attached with fluorophores or other functional groups,and thus making it potentially a versatile pH-controlled molecular switch for designing nanomachines and nanomaterials.
Abstract
DNA is an attractive biomaterial for constructing nanomachines and nanomaterials owing to their self-recognition and self-assembly properties.In addition to the well-known double helical structures,DNA molecules can also form a variety of unusual structures like hairpins,triplexes and quadruplexes.These unusual DNAs sometimes have advantages over double helical DNAs in constructing nanomachines such as enhanced thermodynamic stability and higher sensitivity to external stimuli,which made them as promising motifs in recenttwo decades.Regardless of how complicated DNA-based nanomachines are,the fundamental concept in these nanomachines is based on a proper design and usage of DNA molecular switch.Among the reported DNA molecular switches,pH-controlled systems show great potentials in drug delivery and cellular pH sensing.Up to now,most of the reported pH-controlled molecular switches used i-motif or triplex DNAs.However,owing to the relatively long sequence requirement for the formation of i-motif and triplex DNAs,an invading DNA strand needs to be added to activate the molecular switch,and thus DNA wastes will be generated into the system and a full structural conversion will usually take a relatively long time of minutes to hours.To overcome the disadvantages of DNA waste generation and slow kinetics,molecular switches using smaller-size,thermodynamically stable and pH-sensible unusual DNA structures will have the advantages of easier manipulation and faster kinetics.Recently,we discovered a new type of unusual DNA structure called the minidumbbell(MDB)which is formed by a single-strand 8-nucleotide sequence.The MDB is composed of two type II tetraloops in which the first and fourth loop residues form loop-closing base pairs,the second loop residues fold into the minor groove to form base-base stacking or mispairing interactions,and the third loop residues stack on their nearby loop-closing base pairs.In particular,the MDB formed by a sequence containing two CCTG repeats has a relatively low melting temperature(Tm)of～22℃at pH 7.0,whereas its Tm can be significantly increased to～46℃at pH 5.0 due to the formation of a three hydrogen bond hemiprotonated C+·C mispair in the minor groove.This MDB,when combined with its complementary sequence,shows instant and complete structural conversions when the pH switches between 5.0 and 7.0 without using an invading DNA strand,serving as a simple and efficient pH-controlled molecular switch.In order to allow the incorporation of fluorophores to the two termini of the MDB,we aim to design a thermodynamically more stable MDB structure in this study.Through a rational design by introducing hydrophobic interactions to the MDB formed by the sequence containing two CCTG repeats at pH 5.0,we obtained an MDB structure with a record-high Tm of～62℃.Furthermore,this MDB was found to exist stably in the presence of 5’and 3’-overhanging residues,revealing its capability of being attached with fluorophores or other functional groups,and thus making it potentially a versatile pH-controlled molecular switch for designing nanomachines and nanomaterials.
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