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A sequence-controlled polymer is a
macromolecule A macromolecule is a very large molecule important to biophysical processes, such as a protein or nucleic acid. It is composed of thousands of covalently bonded atoms. Many macromolecules are polymers of smaller molecules called monomers. The ...
, in which the sequence of
monomer In chemistry, a monomer ( ; '' mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization. Classification ...
s is controlled to some degree. This control can be absolute but not necessarily. In other words, a sequence-controlled polymer can be uniform (its dispersity Ð is equal to 1) or non-uniform (Ð>1). For example, an alternating
copolymer In polymer chemistry, a copolymer is a polymer derived from more than one species of monomer. The polymerization of monomers into copolymers is called copolymerization. Copolymers obtained from the copolymerization of two monomer species are ...
synthesized by
radical polymerization In polymer chemistry, free-radical polymerization (FRP) is a method of polymerization by which a polymer forms by the successive addition of free-radical building blocks ( repeat units). Free radicals can be formed by a number of different mechani ...
is a sequence-controlled polymer, even if it is also a non-uniform polymer, in which chains have different chain-lengths and slightly different compositions. A
biopolymer Biopolymers are natural polymers produced by the cells of living organisms. Like other polymers, biopolymers consist of monomeric units that are covalently bonded in chains to form larger molecules. There are three main classes of biopolymers, ...
(for example a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
) with a perfectly-defined
primary structure Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynth ...
is also a sequence-controlled polymer. However, in the case of uniform macromolecules, the term sequence-defined polymer can also be used. With comparison to traditional
polymer A polymer (; Greek '' poly-'', "many" + '' -mer'', "part") is a substance or material consisting of very large molecules called macromolecules, composed of many repeating subunits. Due to their broad spectrum of properties, both synthetic a ...
s, the composition of sequence-controlled polymers can be precisely defined via chemical synthetic methods, such as multicomponent reactions, click reactions etc. Such tunable polymerizing manner endows sequence-controlled polymers with particular properties and thereby, sequence-controlled polymers-based applications (e.g. information storage,
biomaterial A biomaterial is a substance that has been engineered to interact with biological systems for a medical purpose, either a therapeutic (treat, augment, repair, or replace a tissue function of the body) or a diagnostic one. As a science, biomateria ...
s,
nanomaterials * Nanomaterials describe, in principle, materials of which a single unit is sized (in at least one dimension) between 1 and 100 nm (the usual definition of nanoscale). Nanomaterials research takes a materials science-based approach to n ...
etc.) are developed. In nature, DNA, RNA, proteins and other macromolecules can also be recognized as sequence-controlled polymers for their well-ordered structural skeletons. DNA, based on A-T, C-G base pairs, are formed in well-aligned sequences. Through precise sequences of DNA, 20
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
s are able to generate sequential peptide chains with three-dimensional structures by virtue of transcription and
translation Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...
process. These ordered sequences of different constituents endow organisms with complicated and diverse functions.


Synthetic methods

Traditional polymers are usually consist of one repeating unit or several repeating units, arranged in random sequences. Sequence-controlled polymers are composed of different repeating units, which are arranged in an ordered manner. In order to control the sequence, various kinds of synthetic methodologies are developed.


Sequence-controlled biological polymerization

DNA, RNA and proteins are most common sequence-controlled polymers in living creatures. Inspired by them, polymerization methods, utilizing DNA or RNA as templates to control sequences of polymer, are developed. At first, taking DNA or RNA as templates, scientists developed a series of
peptide nucleic acid Peptide nucleic acid (PNA) is an artificially synthesized polymer similar to DNA or RNA. Synthetic peptide nucleic acid oligomers have been used in recent years in molecular biology procedures, diagnostic assays, and antisense therapies. Due to ...
(PNA)-based polymers, without using DNA
polymerase A polymerase is an enzyme ( EC 2.7.7.6/7/19/48/49) that synthesizes long chains of polymers or nucleic acids. DNA polymerase and RNA polymerase are used to assemble DNA and RNA molecules, respectively, by copying a DNA template strand using ba ...
s. But this method is limited to polymerization scale and yield. After that,
polymerase chain reaction The polymerase chain reaction (PCR) is a method widely used to rapidly make millions to billions of copies (complete or partial) of a specific DNA sample, allowing scientists to take a very small sample of DNA and amplify it (or a part of it) ...
(PCR) is developed, which currently is still the most extensively used sequence-regulated method. By employing enzymes, the yields and scales are greatly increased, but the specificity of
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s towards natural peptides limits this technique to a certain degree. Nowadays, more attention is paid to utilization of ribosomes to directly mimic the transcription and translation process. This technology called
protein engineering Protein engineering is the process of developing useful or valuable proteins. It is a young discipline, with much research taking place into the understanding of protein folding and recognition for protein design principles. It has been used to im ...
is considered as the most promising biological polymerization method for synthesis of sequence-controlled polymers.


Sequence-controlled chemical polymerizations

Other than biological polymerization methods, scientists have also developed numerous chemical synthetic methods for sequence-controlled polymers. Compared with biological polymerization, chemical polymerization can provide better diversity but most of the chemical methods cannot offer the efficiency and specificity of biological methods.


Solid-phase synthesis

One of the chemical polymerization methods is solid-phase synthesis, which can be used to synthesize peptides consisted of natural and non-natural amino acids. In this method, the monomers are attached to the polymer chain via amidation between carbonyl group and amino group. For purpose of sequence control, the amino groups are usually protected by 9-fluorenylmethyloxycarbonyl group ( Fmoc) and t-butyloxycarbonyl (Boc), which can be removed under base and acid environment respectively to participate into next-round chain elongation.


Sequence-controlled radical polymerization

Radical polymerization is one of the most commonly used polymerization methods. About 50% of commercially available polymers are synthesized via radical polymerization. However, the disadvantages of this method are apparent that sequences and polymeric features cannot be well modulated. To overcome these constraints, scientists optimized the employed protocols. The first reported example was the time-controlled sequential addition of highly-reactive N-substituted maleimides in the atom transfer radical polymerization of
styrene Styrene () is an organic compound with the chemical formula C6H5CH=CH2. This derivative of benzene is a colorless oily liquid, although aged samples can appear yellowish. The compound evaporates easily and has a sweet smell, although high concen ...
, which led to programmed sequences of functional monomers. The development of single-molecule addition into atom-transfer radical polymerization (ATRP), which enhances the sequence control of radical polymerization was also reported. Other solutions include the use of intermediate purification steps to isolate the desired oligomer sequence in between subsequent reversible addition−fragmentation chain-transfer polymerization (RAFT-polymerizations). Both flash column chromatography and recycling size exclusion chromatography have been proven successful in this regard. RAFT single unit monomer insertion (SUMI) is recently developed as an emerging technology for precise control of monomer sequence.


Sequence controlled non-radical polymerization

For the intrinsic shortages of radical polymerization for sequence-controlled polymers, other non-radical polymerizations are also developed. Within those non-radical methods, azide-alkyne cycloaddition (also known as click reaction),
olefin metathesis Olefin metathesis is an organic reaction that entails the redistribution of fragments of alkenes (olefins) by the scission and regeneration of carbon-carbon double bonds. Because of the relative simplicity of olefin metathesis, it often create ...
among others are utilized to construct sequence-controlled polymers. Depending on these specific chemical reactions, monomers are accurately added to the polymer chain and a well-ordered chain is accomplished stepwise. Meanwhile, by applying multiple chemical reactions, chemists have also developed multi-component reactions to accelerate the construction of polymer skeletons and also enhance variety. Beyond the aforementioned, there was a research group developing a molecule machine, which successfully achieve a sequence-controlled polymerization of
oligopeptide An oligopeptide, often just called peptide ('' oligo-'', "a few"), consists of two to twenty amino acids and can include dipeptides, tripeptides, tetrapeptides, and pentapeptides. Some of the major classes of naturally occurring oligopeptides in ...
s.


Methodology towards improving sequence control

The most important character of sequence-controlled polymers is its controllable sequence of polymer backbone. Nonetheless, to realize a precise sequence control and to regulate sequences in greater polymer backbones are also the most urgent issue, which needs to be addressed in the field of sequence-controlled polymers. Great efforts have been made in development and optimization of methods to improve the sequence-control properties of currently existed synthetic methods and also to further brand-new methods with better synthetic efficiency and sequence control.


Utilization of templates

One of the most significant character of sequence-controlled biosynthesis against other chemical synthetic methods is that the biomolecules (including DNA and RNA) can initiate their polymerization using highly programmed templates. Hence, biosynthetic methods, like PCR, are still considered one of most cogent manner to develop sequence-controlled polymers.


Regulation of reactivity of monomer

To modulate the reactivity between monomer and growing polymeric chain is another approach to enhance sequence control. The rationale for this method is that monomer has to be activated with first
catalyst Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
at beginning as a dormant species, which could then participate into polymerization as the second catalyst is introduced. A real example is utilization of HI as first catalyst and ZnI2 as second catalyst to achieve sequence-controlled polymerization of vinyl ethers and
styrene Styrene () is an organic compound with the chemical formula C6H5CH=CH2. This derivative of benzene is a colorless oily liquid, although aged samples can appear yellowish. The compound evaporates easily and has a sweet smell, although high concen ...
derivatives.


Recognition-oriented insertion

In this approach, a recognition site at polymer is offered to non-covalently anchor the monomer at polymer chain, which can subsequently go through a chemical insertion into polymeric backbone. One successful example demonstrates that
methacrylic acid Methacrylic acid, abbreviated MAA, is an organic compound. This colorless, viscous liquid is a carboxylic acid with an acrid unpleasant odor. It is soluble in warm water and miscible with most organic solvents. Methacrylic acid is produced indu ...
(monomer) can be radically incorporated into a backbone featuring a recognizable cationic site (
protonate In chemistry, protonation (or hydronation) is the adding of a proton (or hydron, or hydrogen cation), (H+) to an atom, molecule, or ion, forming a conjugate acid. (The complementary process, when a proton is removed from a Brønsted–Lowry aci ...
d
primary amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent such ...
pendant). Driven by this site-specific reaction, the sequence-controlled polymerization can be achieve by using a template adorned with differenrt recognizable pendants.


Properties and applications

The most distinguishable feature of sequence-controlled polymers is the well-ordered chains composed of different repeating units. By encoding the repeating units, the correspondingly synthesized sequence-controlled polymer can be used for data storage. To modify the monomer with some bioactive moieties, the obtained sequence-controlled polymer is able to treat diseases. The property of sequence control make sequence-controlled polymers an ideal platform to install various kinds of pendants (like
drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhala ...
s,
catalyst Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
), whereby diverse functions and applications can be realized.


References

{{Reflist Polymers