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Peptide
Peptide
Peptide
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Drosomycin, an example of a peptide

Peptides are short chains of amino acids linked by peptide bonds.[1][2] A polypeptide is a longer, continuous, unbranched peptide chain.[3] Polypeptides that have a molecular mass of 10,000 Da or more are called proteins.[4] Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.

Peptides fall under the broad chemical classes of biological polymers and oligomers, alongside nucleic acids, oligosaccharides, polysaccharides, and others.

Proteins consist of one or more polypeptides arranged in a biologically functional way, often bound to ligands such as coenzymes and cofactors, to another protein or other macromolecule such as DNA or RNA, or to complex macromolecular assemblies.[5]

Amino acids that have been incorporated into peptides are termed residues. A water molecule is released during formation of each amide bond.[6] All peptides except cyclic peptides have an N-terminal (amine group) and C-terminal (carboxyl group) residue at the end of the peptide (as shown for the tetrapeptide in the image).

Classification

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There are numerous types of peptides that have been classified according to their sources and functions. According to the Handbook of Biologically Active Peptides, some groups of peptides include plant peptides, bacterial/antibiotic peptides, fungal peptides, invertebrate peptides, amphibian/skin peptides, venom peptides, cancer/anticancer peptides, vaccine peptides, immune/inflammatory peptides, brain peptides, endocrine peptides, ingestive peptides, gastrointestinal peptides, cardiovascular peptides, renal peptides, respiratory peptides, opioid peptides, neurotrophic peptides, and blood–brain peptides.[7]

Some ribosomal peptides are subject to proteolysis. These function, typically in higher organisms, as hormones and signaling molecules. Some microbes produce peptides as antibiotics, such as microcins and bacteriocins.[8]

Peptides frequently have post-translational modifications such as phosphorylation, hydroxylation, sulfonation, palmitoylation, glycosylation, and disulfide formation. In general, peptides are linear, although lariat structures have been observed.[9] More exotic manipulations do occur, such as racemization of L-amino acids to D-amino acids in platypus venom.[10]

Nonribosomal peptides are assembled by enzymes, not the ribosome. A common non-ribosomal peptide is glutathione, a component of the antioxidant defenses of most aerobic organisms.[11] Other nonribosomal peptides are most common in unicellular organisms, plants, and fungi and are synthesized by modular enzyme complexes called nonribosomal peptide synthetases.[12]

These complexes are often laid out in a similar fashion, and they can contain many different modules to perform a diverse set of chemical manipulations on the developing product.[13] These peptides are often cyclic and can have highly complex cyclic structures, although linear nonribosomal peptides are also common. Since the system is closely related to the machinery for building fatty acids and polyketides, hybrid compounds are often found. The presence of oxazoles or thiazoles often indicates that the compound was synthesized in this fashion.[14]

Peptones are derived from animal milk or meat digested by proteolysis.[15] In addition to containing small peptides, the resulting material includes fats, metals, salts, vitamins, and many other biological compounds. Peptones are used in nutrient media for growing bacteria and fungi.[16]

Peptide fragments refer to fragments of proteins that are used to identify or quantify the source protein.[17] Often these are the products of enzymatic degradation performed in the laboratory on a controlled sample, but can also be forensic or paleontological samples that have been degraded by natural effects.[18][19]

Chemical synthesis

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Main article: Peptide synthesis
Table of amino acids
Solid-phase peptide synthesis on a rink amide resin using Fmoc-α-amine-protected amino acid

Protein-peptide interactions

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Example of a protein (orange) and peptide (green) interaction. Obtained from Propedia: a peptide-protein interactions database.[20]

Peptides can perform interactions with proteins and other macromolecules. They are responsible for numerous important functions in human cells, such as cell signaling, and act as immune modulators.[21] Indeed, studies have reported that 15-40% of all protein-protein interactions in human cells are mediated by peptides.[22] Additionally, it is estimated that at least 10% of the pharmaceutical market is based on peptide products.[21]

Example families

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The peptide families in this section are ribosomal peptides, usually with hormonal activity. All of these peptides are synthesized by cells as longer "propeptides" or "proproteins" and truncated prior to exiting the cell. They are released into the bloodstream where they perform their signaling functions.[23]

Antimicrobial peptides

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Tachykinin peptides

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Main article: Tachykinin peptides

Vasoactive intestinal peptides

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Main article: Secretin family
  • VIP (Vasoactive Intestinal Peptide; PHM27)
  • PACAP Pituitary Adenylate Cyclase Activating Peptide
  • Peptide PHI 27 (Peptide Histidine Isoleucine 27)
  • GHRH 1-24 (Growth Hormone Releasing Hormone 1-24)
  • Glucagon
  • Secretin
[edit]
  • NPY (NeuroPeptide Y)
  • PYY (Peptide YY)
  • APP (Avian Pancreatic Polypeptide)
  • PPY Pancreatic PolYpeptide

Opioid peptides

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Main article: Opioid peptide

Calcitonin peptides

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Self-assembling peptides

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Other peptides

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Terminology

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Length

[edit]

Several terms related to peptides have no strict length definitions, and there is often overlap in their usage:[citation needed]

  • A polypeptide is a single linear chain of many amino acids (any length), held together by amide bonds.
  • A protein consists of one or more polypeptides (more than about 50 amino acids long).
  • An oligopeptide consists of only a few amino acids (between two and twenty).

Number of amino acids

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A tripeptide (example Val-Gly-Ala) with
green marked amino end (L-valine) and
blue marked carboxyl end (L-alanine)

Peptides and proteins are often described by the number of amino acids in their chain, e.g. a protein with 158 amino acids may be described as a "158 amino-acid-long protein". Peptides of specific shorter lengths are named using IUPAC numerical multiplier prefixes:

The same words are also used to describe a group of residues in a larger polypeptide (e.g., RGD motif).

Function

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  • A neuropeptide is a peptide that is active in association with neural tissue.
  • A lipopeptide is a peptide that has a lipid connected to it, and pepducins are lipopeptides that interact with GPCRs.
  • A peptide hormone is a peptide that acts as a hormone.
  • A proteose is a mixture of peptides produced by the hydrolysis of proteins. The term is somewhat archaic.
  • A peptidergic agent (or drug) is a chemical which functions to directly modulate the peptide systems in the body or brain. An example is opioidergics, which are neuropeptidergics.
  • A cell-penetrating peptide is a peptide able to penetrate the cell membrane.

See also

[edit]
Wikiquote has quotations related to Peptide.

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Peptide

View on Grokipedia
from Grokipedia
A peptide is a short chain of amino acids, typically consisting of 2 to 50 residues, linked together by peptide bonds formed through a between the carboxyl group of one and the amino group of another. These molecules, with molecular weights generally below 10,000 Da, differ from proteins, which are longer polypeptides (often exceeding 50 and 30,000 Da) capable of folding into complex three-dimensional structures. This distinction is based on size and functional complexity, with peptides generally not forming the intricate globular structures typical of proteins, though both share the same fundamental building blocks and bonding mechanisms. Peptides can adopt secondary structures such as alpha-helices or beta-sheets and often undergo post-translational modifications like or , enhancing their functionality. In biological systems, peptides serve diverse roles as signaling molecules, hormones, neurotransmitters, and agents, regulating processes such as , immune responses, and cellular communication across all domains of . For instance, endogenous peptides like oxytocin act as hormones to influence reproduction and social behavior, while such as combat bacterial infections by disrupting cell membranes. They are synthesized either ribosomally during protein , which produces linear peptides as part of larger protein precursors, or non-ribosomally by specialized s in microbes and , allowing for structural diversity including linear, cyclic, or branched forms. This versatility enables peptides to interfere with protein-protein interactions, modulate activity, and act as fragments of larger proteins with specific bioactive properties. Peptides hold significant importance in medicine and biotechnology due to their high specificity, biodegradability, and low toxicity compared to small-molecule drugs. Nearly 100 peptide-based therapeutics have been approved worldwide, including insulin for and enfuvirtide for treatment, with global sales surpassing $70 billion in 2019. Advances in solid-phase , pioneered in the mid-20th century, have facilitated their production for applications in , cancer targeting, development, and diagnostics, such as peptide-based agents for tumors. Ongoing focuses on overcoming challenges like poor oral through chemical modifications, expanding their potential in treating metabolic, cardiovascular, and infectious diseases.

Fundamentals

Definition and Overview

A peptide is defined as a short chain of , typically consisting of 2 to 50 residues, linked together by peptide bonds, which are linkages formed through synthesis between the carboxyl group of one and the amino group of another. These molecules represent an intermediate scale between individual and larger polypeptides, with their sequence determining specific structural and functional properties. As naturally occurring signaling molecules, peptides influence a range of physiological processes, including tissue healing, hormone release, metabolism, immune function, and aspects of aging. The history of peptide research traces back to the early 20th century, when first synthesized the glycylglycine in 1901 through partial of anhydride, marking the inaugural of a peptide. In 1902, coined the term "peptide" to describe these chains, drawing an analogy to , while independently, Franz Hofmeister proposed that proteins consist of connected by similar bonds. Peptides are distinguished from proteins primarily by length: proteins generally comprise more than 50 and often fold into complex three-dimensional structures to perform diverse cellular functions, whereas peptides remain relatively linear and compact. Oligopeptides, a of peptides, are even shorter, usually containing 10 to 20 , and exhibit simpler conformations without extensive secondary structures. In , peptides serve as essential building blocks for the synthesis of proteins during ribosomal , while also functioning independently as signaling molecules, hormones such as insulin, and antimicrobial agents like . These roles enable peptides to regulate physiological processes, including cell communication and immune defense. Evolutionarily, peptides hold significance in prebiotic chemistry, where short chains likely acted as primitive catalysts, facilitating early metabolic reactions on the primordial Earth before the emergence of modern enzymes.

Structure and Composition

Peptides are composed of residues linked by peptide bonds, which form through a between the carboxyl group of one and the amino group of another, releasing a molecule and creating an amide linkage. This amide bond exhibits partial double-bond character due to delocalization of the pi electrons from the carbonyl oxygen to the nitrogen atom, resulting in a rigid, planar where the carbonyl carbon, oxygen, nitrogen, and attached hydrogen lie in the same plane. The trans configuration predominates in peptide bonds because it minimizes steric hindrance between adjacent side chains, with the cis form being rare except in specific cases like proline residues. The general structure of a dipeptide can be represented as \ceR1−CH(NH2)−CO−NH−CH(R2)−COOH\ce{R^1-CH(NH2)-CO-NH-CH(R^2)-COOH}, where R1R^1 and R2R^2 are the side chains of the constituent . Peptides are primarily built from the 20 standard L-, each distinguished by its unique (R group) that imparts diverse properties such as hydrophobicity (e.g., , ), hydrophilicity (e.g., serine), or charge (e.g., positively charged and ; negatively charged aspartate and glutamate). These variations influence the overall folding, stability, and interactions of the peptide. In their basic form, peptides adopt linear chains of residues, but structural diversity arises through cyclization, such as head-to-tail lactamization or side-chain linkages, which constrain flexibility and enhance stability against enzymatic degradation. bridges, formed by oxidation of cysteine groups, represent a common side-chain-to-side-chain cyclization that stabilizes three-dimensional structures, as seen in peptides like . Post-translational modifications further diversify peptide composition and function. adds a phosphate group to serine, , or residues, modulating bioactivity, while attaches moieties to serine or , influencing stability and receptor binding. C-terminal amidation, converting the carboxyl group to an amide, enhances potency and resistance to , as in oxytocin, which also features a bridge between cysteines and a cyclic for rigidity. Peptides predominantly incorporate L-amino acids due to the homochiral nature of ribosomal biosynthesis in living organisms, with the chiral center at the alpha carbon adopting the L-configuration (S in Cahn-Ingold-Prelog nomenclature, except for ). However, D-amino acids appear in certain bacterial peptides, such as D-alanine in peptidoglycans and gramicidin S, conferring resistance to and enhancing activity.

Terminology and Conventions

Length and Size Designation

Peptides are categorized by the number of residues in their chain, with specific terms denoting different lengths. A consists of two linked by a single , while a contains three and two s. typically comprise between 2 and 20 , encompassing short chains that exhibit limited structural complexity. Polypeptides are generally chains with more than 20 , which may extend to larger structures approaching those of proteins depending on the biochemical context. There is no universally strict cutoff distinguishing peptides from proteins, as the boundary is often arbitrary and context-dependent, such as in biochemistry where molecular weight or functional roles may influence classification. For instance, one common delineation sets proteins at molecular weights exceeding 5,000 Da, while peptides fall below this threshold. The typical molecular mass range for peptides is 200 to 10,000 Da, reflecting their shorter lengths compared to proteins, which often exceed 30,000 Da. The length of a peptide significantly influences its physical properties, particularly flexibility and propensity for secondary . Shorter peptides, such as dipeptides and tripeptides, tend to be highly flexible due to fewer constraints on backbone , allowing greater conformational freedom in solution. In contrast, longer peptides within the or polypeptide range are more likely to adopt stable secondary structures, such as α-helices or β-turns, as the increased chain length stabilizes hydrogen bonding patterns. Special cases in peptide length designation include cyclic peptides, where size is measured by the number of forming the ring, influencing rigidity and —for example, rings of 10 to 16 residues can alter conformational preferences. Depsipeptides represent another variant, defined as peptides incorporating one or more bonds alongside traditional peptide () bonds, with length still counted by the total number of residues but exhibiting modified stability due to the hybrid linkages.

Naming and Sequence Notation

Peptides are named according to IUPAC recommendations, which specify systematic for small peptides by combining the names of constituent , with the N-terminal residue expressed as an ending in "-yl" and the C-terminal residue retaining its full name, implying the free carboxyl group. For example, the consisting of linked to is named alanylglycine, reflecting the H-Ala-Gly-OH, where the N-terminal and C-terminal are standard unless modified. Configurational specifications, such as L- or D-, are prefixed to each residue name when needed, as in L-alanylglycine for the naturally occurring form. In , peptide sequences are conventionally notated from the (left) to the (right) to reflect the directional polarity of the . The three-letter code system, recommended by IUPAC-IUB, uses abbreviated trivial names for connected by hyphens (e.g., Ala-Gly for alanylglycine), facilitating readability for short sequences. For longer sequences, the one-letter code system is preferred, employing uppercase letters without hyphens or spaces (e.g., AG for alanylglycine), as it allows compact representation and easy alignment in alignments or databases. Modifications are indicated by prefixes or parentheses; for instance, N-terminal is denoted as Ac-Ala-Gly in either code system. A representative example is the bradykinin, whose is notated as Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg in three-letter code or RPPGFSPFR in one-letter code, highlighting the use of these conventions in biological contexts. Ambiguities in determination are resolved using symbols like X or Xaa to denote unknown residues, as standardized in protein databases where may not resolve specific identities. For isotopic labeling, notations such as ¹³C-Ala specify enrichment in , commonly employed in for without altering the core rules.

Synthesis Methods

Biological Synthesis

Peptides in living organisms are primarily synthesized through ribosomal and non-ribosomal pathways, which enable the production of diverse bioactive molecules essential for cellular functions. The ribosomal pathway accounts for the vast majority of peptide and protein synthesis, utilizing the to assemble linear polypeptides that often serve as precursors to mature peptides. In the ribosomal synthesis process, (mRNA) transcripts are translated by ribosomes into polypeptide chains, a mechanism that occurs universally across eukaryotes and prokaryotes. This translation begins in the , where ribosomes—either free or bound to the rough (RER)—read the mRNA sequence in triplets (codons) and incorporate corresponding via transfer RNAs (tRNAs), forming peptide bonds to elongate the chain. For secretory peptides, such as hormones and neuropeptides, synthesis initiates on RER-bound ribosomes, directing the nascent chain into the endoplasmic reticulum lumen. The initial product is typically a prepropeptide, which includes an N-terminal that targets it to the ER for translocation and subsequent processing. Post-translational is crucial to generate mature peptides from ribosomal precursors, involving proteolytic cleavages and modifications. In the ER, the is cleaved by signal peptidase, yielding a propeptide form. Further occurs in the Golgi apparatus and secretory vesicles, where propeptidases remove connecting segments, and additional modifications such as cyclization, amidation, or may take place to stabilize the structure and enhance bioactivity. A representative example is insulin in pancreatic beta cells, where preproinsulin (110 ) is translated on RER-bound ribosomes, translocated into the ER for removal to form proinsulin, and then cleaved in secretory granules by convertases to yield mature insulin and . Neuropeptides, such as those in neurons, follow a similar route, with synthesis in the neuronal cell body at the RER, through the Golgi, and packaging into dense-core vesicles for and release. A specialized subclass of ribosomally synthesized peptides are the ribosomally synthesized and post-translationally modified peptides (RiPPs), which are produced from ribosomally translated precursor peptides that undergo extensive tailoring by dedicated biosynthetic enzymes. These modifications, such as , cyclization, and heterocyclization, generate diverse structures with bioactivities like and cytotoxic effects, predominantly in but also in , eukaryotes, and . RiPPs include classes like lanthipeptides, thiopeptides, and lasso peptides, with biosynthesis involving leader peptide recognition for modification of the core region. The non-ribosomal peptide synthesis (NRPS) pathway, in contrast, operates independently of ribosomes and is mediated by large multimodular enzymes called non-ribosomal peptide synthetases (NRPSs), predominantly in and fungi. These megasynthases assemble peptides via a thiotemplated mechanism, activating as aminoacyl-adenylates and sequentially condensing them on carrier domains, allowing incorporation of non-proteinogenic residues like D-, hydroxy acids, and polyketide-derived units. NRPS modules typically include adenylation, peptidyl carrier protein, and condensation domains, enabling iterative or non-iterative elongation to produce cyclic or linear structures with high structural diversity. Unlike ribosomal synthesis, NRPS does not rely on mRNA templates, facilitating rapid of peptide sequences for specialized functions. Processing in the NRPS pathway often includes epimerization, cyclization via thioesterase domains, and glycosylation, occurring concurrently with assembly on the enzyme scaffold. Exemplary products include the beta-lactam antibiotic penicillin, synthesized by fungal NRPS (e.g., ACV synthetase in Penicillium) from aminoadipate, cysteine, and valine with cyclization to form the core ring, and vancomycin, a glycopeptide antibiotic produced by bacterial NRPS in actinomycetes, incorporating chlorinated tyrosine derivatives and featuring a macrocyclic heptapeptide structure. These pathways are localized in prokaryotic cytoplasm or fungal organelles, with NRPS clusters often clustered in genomes for coordinated expression.

Chemical Synthesis

Chemical synthesis of peptides involves laboratory-based methods to assemble chains through bond formation, distinct from biological processes. These techniques enable the production of custom peptides for research and therapeutic applications, with solid-phase (SPPS) emerging as the dominant approach since its invention. The foundational method, SPPS, was developed by Robert Bruce Merrifield in 1963, allowing sequential addition of protected anchored to an insoluble support, which facilitates purification by filtration after each step. In this process, the C-terminal is first attached to the , and subsequent are added from the C- to N-terminus using a cycle of deprotection, coupling, and washing. Early implementations employed tert-butoxycarbonyl (Boc) as the Nα-protecting group, which is removed under acidic conditions like , while side-chain protections are cleaved simultaneously at the end. Boc-SPPS requires repetitive acid-base treatments to neutralize the after deprotection, making it labor-intensive but effective for peptides up to 50 residues. An alternative strategy, the 9-fluorenylmethoxycarbonyl (Fmoc) , was adapted for SPPS in the late 1970s by Sheppard and colleagues, offering milder, base-labile deprotection with , which avoids cumulative damage from strong acids. Fmoc-SPPS has become the standard due to its —Fmoc removal does not affect acid-labile side-chain protections like tert-butyl groups—and higher yields for longer sequences, often achieving purities above 80% after (HPLC) purification. Coupling in both strategies typically uses activating agents such as dicyclohexylcarbodiimide (DCC) or more modern reagents like O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium (HBTU) to form the amide bond efficiently. For smaller peptides (typically under 10 residues), solution-phase synthesis remains viable, involving stepwise or fragment in homogeneous media. This classical approach, predating SPPS, relies on selective and deprotection of , with DCC introduced by Sheehan and Hess in as a key agent that promotes dehydration between and groups while minimizing side reactions. Solution methods allow precise control over reaction conditions but require extensive purification after each , limiting scalability for longer chains. Yields can reach 90% per step with optimized conditions, though overall efficiency drops exponentially with chain length. The core steps in SPPS include: (1) deprotection of the N-terminal to expose the free ; (2) of the incoming protected amino acid's carboxyl group and its to the resin-bound chain, monitored by tests like the for completeness; and (3) final cleavage from the resin (e.g., with for Boc or for Fmoc) followed by side-chain deprotection and purification via HPLC or gel filtration. Peptide purity is assessed by reverse-phase HPLC, with analytical yields often exceeding 70% for sequences up to 30 using Fmoc chemistry. Significant challenges in chemical peptide synthesis include racemization during coupling, where the activated amino acid can form an oxazolone intermediate leading to partial D-isomer formation, particularly with residues like serine or histidine—rates can approach 5-10% without additives like hydroxybenzotriazole (HOBt). Aggregation of growing chains on the resin, driven by β-sheet formation in hydrophobic sequences, impedes solvent access and coupling efficiency, often requiring chaotropic additives like guanidinium chloride or elevated temperatures. For sequences beyond 50 residues, stepwise yields compound to low overall efficiency (e.g., <1% for 100-mers), prompting hybrid strategies combining chemical synthesis with recombinant expression of peptide segments. Modern advances have addressed these issues through microwave-assisted SPPS, which accelerates deprotection and coupling by 10- to 100-fold via , reducing reaction times to minutes per cycle while minimizing when temperatures are controlled below 75°C. Automated synthesizers, such as flow-based systems from CEM or CSBio, integrate real-time monitoring, parallel processing, and green solvents like , enabling gram-scale production of peptides with purities over 95% in under 24 hours. These instruments, evolved since the , support high-throughput synthesis and have facilitated the routine preparation of complex peptides for .

Properties and Interactions

Physical and Chemical Properties

The solubility of peptides is primarily governed by the hydrophilicity or hydrophobicity of their side chains. Polar and charged residues, such as and , promote aqueous through favorable interactions with molecules, whereas hydrophobic residues like and tend to reduce it, potentially leading to aggregation. For instance, , rich in positively charged side chains, demonstrates high across a wide range. Peptide stability is influenced by both chemical and physical factors, with the bonds forming the peptide backbone being particularly vulnerable to . This is pH-dependent, occurring more rapidly at extreme acidic or basic conditions due to or of the , which facilitates nucleophilic attack. Additionally, peptides are prone to enzymatic degradation by proteases, which cleave peptide bonds at specific sequences, leading to short half-lives in biological environments. Furthermore, proper storage conditions are essential for maintaining stability; reconstituted peptides typically require refrigeration at 2-8°C (36-46°F) to preserve potency. The conformation of peptides encompasses secondary structures such as α-helices and β-sheets, which are stabilized primarily by intramolecular hydrogen bonds between the carbonyl oxygen of one residue and the amide hydrogen of another, typically four residues apart in helices or between adjacent strands in sheets. These structures contribute to the overall rigidity and functional shape of peptides. spectroscopy is a key analytical technique for characterizing these conformations, as it measures differential absorption of left- and right-circularly polarized light, providing signatures for helical (negative bands at 222 nm and 208 nm) and sheet (negative band at 218 nm) content. The (pI) of a peptide represents the at which it carries no net electrical charge, calculated as the average of the pKa values of its ionizable groups, including the α-amino, α-carboxyl, and functionalities like those in or . This property is crucial for techniques such as , where peptides migrate based on their charge relative to the buffer ; at pH = pI, migration ceases due to neutrality. Peptides exhibit optical activity arising from the chiral α-carbon centers in their L-amino acid constituents, which lack a plane of symmetry and thus rotate the plane of polarized . This is quantified by [α], defined as the observed rotation angle divided by the product of concentration and path length, typically measured at the sodium D-line (589 nm) ./03%3A_Conformations_and_Stereochemistry/3.06%3A_Optical_Activity)

Binding and Interactions

Peptides engage in specific interactions with proteins through recognition of short linear motifs, such as the proline-rich PXXP sequences that bind to SH3 domains, enabling modular protein-protein associations in signaling pathways. These interactions are characterized by their affinity, often quantified by the (Kd), which typically ranges from micromolar to nanomolar values depending on the motif and domain context; for instance, SH3 domains exhibit Kd values in the low micromolar range for canonical ligands. The specificity arises from complementary surface topologies, where the domain's hydrophobic pockets accommodate the peptide's conformation.0251-4) In receptor binding, peptides achieve high specificity through a combination of hydrogen bonding, van der Waals forces, and electrostatic interactions with G-protein coupled receptors (GPCRs), as seen in peptide hormones like (GLP-1) that activate GLP-1R by engaging extracellular loops and the transmembrane core. These non-covalent forces stabilize the peptide-receptor complex, with hydrogen bonds forming between polar side chains and receptor residues, while van der Waals contacts enhance hydrophobic packing; electrostatic interactions further contribute in charged environments.30650-X) Such binding often triggers receptor activation, leading to downstream signaling cascades. Upon binding, peptides can induce conformational changes in target proteins via the , where the stabilizes a specific protein conformation, or through conformational selection, as observed in large-scale rearrangements during protein-peptide docking. In enzyme inhibition, peptides may exert allosteric effects by binding distant sites, altering the active site's geometry and reducing catalytic efficiency, exemplified by allosteric peptide inhibitors of the BACE1 that modulate amyloid-beta production. These dynamics highlight peptides' role in regulating protein function beyond simple occupancy. Therapeutically, peptides serve as potent inhibitors in protease assays, where they mimic substrates to block enzymatic activity, such as cyclic peptides targeting the HCV NS3/4A with high selectivity. Multivalency enhances binding in peptide arrays, where multiple tethered peptides increase overall affinity through cooperative effects, improving detection and inhibition in diagnostic and drug screening applications. This approach leverages gains, often boosting effective Kd by orders of magnitude compared to monovalent interactions. Experimental elucidation of these interactions relies on techniques like (NMR) spectroscopy for dynamic structural insights, for high-resolution complex snapshots, and (SPR) for real-time kinetic measurements of association and dissociation rates. NMR reveals transient states and conformational ensembles, while X-ray provides atomic details of bound poses; SPR quantifies affinities with minimal sample requirements, enabling high-throughput analysis. These methods collectively inform peptide design for therapeutic optimization.

Classification

Structural Classification

Peptides are classified structurally based on their architectural and backbone configurations, which influence their stability, conformation, and potential applications independent of biological function. This classification encompasses linear, cyclic, branched, modified backbone, and self-assembling forms, each offering distinct physicochemical properties. Linear peptides represent the most fundamental and prevalent structural class, consisting of unbranched chains of amino acids linked sequentially by peptide bonds between the carboxyl group of one residue and the amino group of the next. These straight-chain molecules, often ranging from dipeptides to longer polypeptides, adopt flexible conformations that can form secondary structures like alpha-helices or beta-sheets depending on sequence and environment. A classic example is , a (γ-glutamyl-cysteinyl-glycine) that serves as an , illustrating the simplicity and versatility of linear architectures. Cyclic peptides feature a closed-ring formed by covalent linkages that constrain the backbone, typically through head-to-tail bonds or side-chain connections such as bridges, resulting in enhanced proteolytic stability and rigidity compared to linear counterparts. Head-to-tail cyclization connects the N- and C-termini, while side-chain linkages, often involving residues, create looped structures that restrict flexibility and promote defined conformations. This stability arises from reduced loss upon binding and resistance to exopeptidase degradation. Cyclosporin A, an 11-residue cyclic undecapeptide produced by fungi, exemplifies head-to-tail cyclization and is renowned for its immunosuppressive activity due to its compact, conformationally constrained structure. Branched peptides incorporate multiple peptide chains radiating from a central core, often constructed using polylysine scaffolds to amplify valency and enhance multimeric presentation. This architecture allows for the attachment of several identical or diverse linear sequences to a branching point, improving solubility, immunogenicity, and targeted interactions without altering individual chain sequences. A prominent application is in multiple antigen peptides (MAPs), where a core of lysine residues supports up to eight or more peptide arms, facilitating vaccine design by presenting multiple epitopes simultaneously to elicit robust immune responses. The Tam group pioneered this MAP system in the late 1980s, demonstrating its utility in mimicking protein surfaces. Peptides with modified backbones, known as peptidomimetics, deviate from the standard alpha-amino acid linkages to incorporate non-natural connections that mimic or enhance native peptide properties, such as metabolic stability and receptor selectivity. These modifications include beta-peptides, where amino acids are shifted by an extra methylene group to form beta-amino acids, enabling left-handed helical structures resistant to proteolysis; azapeptides, featuring aza-amino acids with nitrogen replacing the alpha-carbon to alter hydrogen bonding; and retro-inverso isomers, which reverse the backbone direction while using D-amino acids to preserve side-chain topography and topological chirality. Such alterations maintain bioactivity while circumventing enzymatic degradation, as seen in retro-inverso analogs of cell-penetrating peptides that improve cellular uptake. Self-assembling peptides constitute a dynamic structural class that spontaneously organizes into higher-order nanostructures through non-covalent interactions like hydrogen bonding and hydrophobic effects, often driven by beta-sheet motifs. These peptides, typically short sequences with alternating charged and hydrophobic residues, form nanofibers, hydrogels, or nanotubes under physiological conditions, offering and tunable responsiveness for applications. The ionic self-complementary peptide RADA16 (Ac-RADARADARADARADA-NH2), with its repeating arginine-alanine-aspartic acid motif, exemplifies beta-sheet-driven assembly into stable nanofibers approximately 10 nm in diameter, used in scaffolds due to their rapid gelation and support for .

Functional Classification

Peptides are classified functionally based on their biological roles and activities, encompassing a diverse array of physiological regulations and therapeutic potentials. This classification emphasizes purpose-driven categories, such as signaling, defense, inhibition, and , often enabled by specific structural motifs like alpha-helices or beta-sheets that facilitate their interactions. Hormonal peptides primarily regulate physiological processes through endocrine signaling, acting as messengers to control , growth, and . For instance, insulin, a 51-amino-acid peptide, modulates in cells to manage , while (GLP-1) analogues such as influence insulin secretion and appetite in treatment. These peptides bind to G-protein-coupled receptors to initiate cascades that maintain . Antimicrobial peptides (AMPs) function by disrupting microbial membranes, providing innate immune defense against , fungi, and viruses. Many AMPs, particularly cationic alpha-helical types like cathelicidins, adopt amphipathic structures that permeabilize negatively charged microbial membranes through electrostatic interactions and pore formation. Examples include periplanetasin-2, which targets difficile infections, highlighting their role in combating antibiotic-resistant pathogens. Neuropeptides modulate by acting as excitatory or inhibitory signals in the , influencing , perception, and . They typically bind to neuronal receptors to alter activity or second messenger systems; for example, oxytocin and its analogue facilitate social bonding and , respectively, demonstrating their regulatory impact on neural circuits. Enzyme inhibitor peptides exert their function through competitive binding to enzyme active sites, thereby blocking substrate access and modulating enzymatic activity in processes like or . These peptides often mimic natural substrates; representative cases include (ACE) inhibitors derived from , which reduce by preventing angiotensin II formation. Structural peptides contribute to the by forming motifs that provide mechanical support and tissue integrity, such as the Gly-Pro-Hyp repeats in collagen-like sequences that enable triple-helix assembly. Short collagen-derived peptides, like those containing RGD motifs, facilitate and matrix organization in tissues such as and . Emerging functional classes of peptides include , which enhance immune responses by promoting and release, as seen in self-assembling peptide nanostructures that boost T-cell activation in peptide-based against cancers and viruses. Additionally, agents leverage peptides' targeting specificity for diagnostic purposes; for example, GEBP11 peptides bind tumor vasculature to enable fluorescence or radiolabeled visualization of gastric cancer lesions.

Biological Significance and Examples

Hormonal and Regulatory Peptides

Hormonal and regulatory peptides are short chains of that function as signaling molecules in endocrine systems, primarily regulating metabolic processes such as glucose , calcium balance, and gastrointestinal functions. These peptides are typically synthesized as larger precursors and exhibit short plasma half-lives, necessitating precise control of their secretion and receptor interactions to maintain physiological balance. Key examples include insulin, , (VIP), (PP), and calcitonin, each with distinct structures and roles in systemic regulation. From an evolutionary standpoint, these peptides have played conserved roles in metabolic regulation across vertebrates, highlighting their ancient origins in endocrine signaling. Insulin, a 51-residue consisting of two chains (A chain of 21 residues and B chain of 30 residues) linked by disulfide bonds, is secreted by pancreatic β-cells and plays a central role in promoting into cells and inhibiting hepatic glucose production. Its deficiency or dysfunction leads to and is a hallmark of diabetes mellitus. Insulin binds to the , a receptor, triggering intracellular signaling cascades that facilitate anabolic processes. The plasma of insulin is approximately 3-10 minutes, reflecting rapid clearance primarily by the liver and kidneys. Glucagon, a 29-residue linear produced by pancreatic α-cells, acts antagonistically to insulin by stimulating and in the liver to raise blood glucose levels during or . It exerts its effects through binding to the , a G-protein-coupled receptor (GPCR) that activates adenylate cyclase and increases cyclic AMP levels. The plasma half-life of glucagon is 3-6 minutes, ensuring quick responsiveness to metabolic needs. (VIP), a 28-residue peptide belonging to the glucagon-secretin superfamily, is released from neurons in the gut and promotes , smooth muscle relaxation, and inhibition of secretion. VIP interacts with VPAC1 and VPAC2 receptors, both GPCRs, to modulate cyclic AMP signaling and exert regulatory effects on cardiovascular and gastrointestinal systems. Its plasma half-life is less than 1 minute, contributing to its role in rapid, localized responses. Pancreatic polypeptide (PP), a 36-residue peptide with a characteristic PP-fold structure, is secreted by F-cells in the in response to intake and inhibits pancreatic exocrine and secretions while also suppressing appetite. PP is structurally related to and binds primarily to the Y4 receptor subtype, a GPCR that influences energy balance. Its plasma half-life is about 7 minutes, limiting its duration of action postprandially. Calcitonin, a 32-residue peptide with an intramolecular bond, is produced by thyroid C-cells and functions to lower blood calcium levels by inhibiting activity and promoting renal calcium excretion. It binds to the calcitonin receptor, a GPCR coupled to Gs proteins, which inhibits . The plasma half-life of calcitonin is approximately 60 minutes, allowing for sustained hypocalcemic effects. These peptides are synthesized as larger precursors—such as preproinsulin for insulin, for , prepro-VIP for VIP, prepro-PP for PP, and preprocalcitonin for calcitonin—which undergo posttranslational processing in the and Golgi apparatus, including cleavage by prohormone convertases and amidation or disulfide bond formation to yield the mature active forms. Receptor interactions generally involve high-affinity binding that activates downstream pathways like cAMP production or cascades, with short half-lives necessitating continuous or for effective regulation.

Antimicrobial and Defensive Peptides

Antimicrobial and defensive peptides represent a crucial component of innate immunity, functioning as host defense molecules that combat microbial invaders through direct killing and modulation of immune responses. These peptides, often cationic and amphipathic, are produced by various organisms, including humans, and exhibit broad-spectrum activity against , fungi, viruses, and parasites. Their evolutionarily conserved structures enable rapid deployment at sites, such as epithelial barriers and immune cells, where they disrupt microbial integrity or interfere with essential cellular processes. Evolutionarily, antimicrobial peptides constitute an ancient component of innate immunity, predating the development of adaptive immune systems and providing a foundational defense mechanism across diverse species. Cationic antimicrobial peptides (AMPs), such as those belonging to the magainin family, are exemplary in this category, derived from amphibian skin secretions like those of the Xenopus laevis. Magainin-2, a 23-residue α-helical peptide, exemplifies membrane disruption mechanisms, including the carpet model, where peptides accumulate on the surface to form micelle-like structures that destabilize and lyse the , and the barrel-stave model, wherein peptides insert perpendicularly to form transmembrane pores lined by their hydrophobic faces. These actions preferentially target negatively charged bacterial membranes due to electrostatic attraction, sparing host cells with zwitterionic lipids. Defensins, another major class of defensive peptides, feature compact β-sheet structures stabilized by three disulfide bonds, conferring resistance to proteolysis and enabling targeted antimicrobial action. In humans, α-defensins (e.g., from neutrophils) and β-defensins (e.g., human β-defensin 2, expressed in epithelial cells) differ in cysteine spacing and tissue distribution but share pore-forming capabilities via toroidal models, where peptides bend the to create water-filled channels. Human β-defensin 2, inducible by microbial stimuli, exhibits potent activity against Gram-positive and by permeabilizing membranes and recruiting immune cells through chemokine-like functions. Cathelicidins, synthesized as inactive propeptides and cleaved to mature forms, provide versatile defense; the cathelicidin LL-37, a 37-residue α-helical peptide, arises from proteolytic processing of hCAP-18 and displays broad-spectrum efficacy against , enveloped viruses, and fungi. LL-37 disrupts membranes via carpet-like coverage and can translocate intracellularly to inhibit synthesis and protein production, enhancing its lethality against pathogens like and . Beyond membrane targeting, some antimicrobial peptides employ intracellular mechanisms, such as binding to DNA/RNA to block replication or inhibiting chaperone proteins like DnaK to disrupt folding, which amplifies their bactericidal effects without relying solely on lysis. Pathogens, however, can evolve resistance through strategies like protease secretion, efflux pumps, or membrane modifications, though such adaptations often impose fitness costs, evolving more slowly than resistance to conventional antibiotics. Therapeutically, antimicrobial peptides hold promise as alternatives to dwindling antibiotics, with derivatives like synthetic LL-37 analogs advancing in clinical trials for wound infections and due to their low resistance propensity. Challenges persist, including host from off-target membrane interactions, proteolytic instability , and high production costs, necessitating engineered variants for improved selectivity and .

Neuropeptides and Signaling Peptides

Neuropeptides serve as key signaling molecules in the , functioning as neurotransmitters or neuromodulators to regulate neuronal activity, , and behavioral responses. These short peptide chains, typically comprising 3 to 40 , are synthesized in neuronal cell bodies and transported to terminals for release. Unlike classical small-molecule neurotransmitters, neuropeptides often exert modulatory effects through volume transmission, influencing broader neural circuits over extended timescales. In the context of signaling peptides, they play critical roles in , emotional , and , primarily by binding to G protein-coupled receptors (GPCRs) on target cells. Evolutionarily, neuropeptides have diverse origins, with many initially identified as pituitary or gastrointestinal hormones, underscoring their conserved roles in neural and physiological regulation across species. Opioid peptides represent a prominent class of neuropeptides involved in analgesia and reward processing. and enkephalins, derived from larger prohormones like pro-opiomelanocortin and proenkephalin, bind preferentially to mu (μ) and delta (δ) opioid receptors to inhibit nociceptive signaling in the and . For example, , a pentapeptide with the sequence Tyr-Gly-Gly-Phe-Met, acts as a selective δ-opioid receptor agonist, suppressing ascending pain pathways by hyperpolarizing neurons and reducing release. These peptides contribute to stress-induced analgesia and modulation of mood, highlighting their role in integrating sensory and emotional responses. Tachykinins, another family of signaling peptides, mediate inflammatory and nociceptive processes. Substance P, an undecapeptide consisting of 11 residues, is released from primary afferent neurons and binds to neurokinin 1 (NK1) receptors to promote pain transmission and neurogenic inflammation. Neurokinin A, a related decapeptide, similarly activates NK1 and NK2 receptors, enhancing vascular permeability and immune cell recruitment in inflamed tissues. These actions amplify sensory signals in conditions like and , underscoring tachykinins' pro-inflammatory effects. Oxytocin and exemplify neuropeptides with diverse regulatory functions. Both are nonapeptides featuring a cyclic formed by a bond between residues at positions 1 and 6, differing by only two . Oxytocin facilitates social bonding, trust, and maternal behaviors by activating oxytocin receptors in regions like the and . , in contrast, maintains through effects on the kidneys via V2 receptors and modulates social recognition and aggression through V1a receptors in the . These peptides highlight the intersection of neural signaling and physiological . Signaling mechanisms of neuropeptides involve GPCR activation, which triggers downstream pathways such as hydrolysis or modulation to alter neuronal excitability. Neuropeptides are frequently co-released with classical neurotransmitters like glutamate or GABA from the same vesicles, allowing synergistic modulation of synaptic strength—enhancing excitation during high-frequency firing or prolonging inhibitory effects. Their extracellular lifespan is limited by rapid degradation through membrane-bound peptidases, including neutral endopeptidase (NEP) and aminopeptidase N, which cleave peptide bonds to prevent prolonged signaling. This enzymatic inactivation ensures precise temporal control of neural responses. Dysregulation of neuropeptide systems underlies several neuropsychiatric disorders, including and anxiety. In , altered opioid peptide signaling in reward circuits contributes to dependence and , as chronic drug exposure downregulates μ-opioid receptor sensitivity. Similarly, imbalances in tachykinin or systems exacerbate anxiety by heightening stress responses in the . Therapeutic strategies target these pathways; for instance, semi-synthetic analogs like , a potent μ-opioid receptor , provide analgesia but risk due to their high efficacy and rapid onset. Ongoing research explores selective peptide analogs to mitigate these adverse effects while preserving therapeutic benefits.

Other Specialized Peptides

Self-assembling peptides represent a class of designer peptides engineered to spontaneously form ordered nanostructures, such as nanofibers and hydrogels, through non-covalent interactions including hydrogen bonding and hydrophobic effects. These peptides often incorporate beta-sheet motifs that drive the assembly process, enabling applications in where they mimic the to support cell growth and differentiation. For instance, the peptide EAK16, a 16-residue with alternating charged (AEAEAKAKAEAEAKAK), self-assembles into stable hydrogels under physiological conditions, providing a biocompatible scaffold for and neural tissue repair. Similarly, RADA16, a related ionic self-complementary peptide, forms networks that enhance and proliferation in . Amyloid peptides are short sequences prone to forming insoluble beta-sheet-rich aggregates, which play pathological roles in neurodegenerative diseases. The amyloid-beta peptide (Aβ1-42), a 42-residue fragment derived from amyloid precursor protein, exemplifies this class by aggregating into that deposit as plaques in the , contributing to progression through and . Structural studies reveal that Aβ1-42 adopts a parallel, in-register beta-sheet conformation in its fibrillar form, with residues 18-42 forming the core beta-strand-turn-beta-strand motif stabilized by intermolecular hydrogen bonds. These aggregates disrupt cellular , underscoring the dual nature of peptides as both disease agents and models for in design. Conotoxins, venom peptides produced by marine cone snails of the genus Conus, are disulfide-rich molecules typically comprising 10-30 amino acids that target ion channels and receptors with high specificity and potency. These peptides feature multiple cysteine residues forming compact disulfide bridges, which confer structural stability and enable rapid prey immobilization by modulating neuronal signaling. For example, α-conotoxins block nicotinic acetylcholine receptors, while ω-conotoxins inhibit voltage-gated calcium channels, demonstrating nanomolar affinities that have inspired analgesic drug development. Their evolutionary diversity, with over 10,000 unique sequences identified across Conus species, highlights their role as natural libraries for pharmacological tools. Plant-derived cyclotides constitute a family of stable cyclic peptides, approximately 30 residues in length, characterized by a head-to-tail cyclized backbone and a cystine motif formed by three interleaved bonds. This knotted structure imparts exceptional resistance to proteolytic degradation and , allowing cyclotides to function in plant defense against pests and pathogens by disrupting cell membranes or inhibiting enzymes. Isolated from species like Oldenlandia affinis, kalata B1 exemplifies this class with its beta-sheet-dominated fold that enables membrane permeabilization and insecticidal activity. Their stability has positioned cyclotides as scaffolds for grafting bioactive epitopes in agricultural and therapeutic applications. In biomedical contexts, specialized peptides have advanced for targeted therapies, including mimics that replicate host-defense mechanisms and self-assembling vehicles for . Post-2020 innovations feature peptide nanostructures like nanofibrils and nanoparticles that encapsulate chemotherapeutics, improving and reducing off-target effects through pH-responsive disassembly. For instance, cyclotide-based conjugates and amyloid-inspired serve as carriers for antibiotics, enhancing efficacy against resistant via membrane disruption. These developments emphasize peptides' versatility in creating biocompatible for and delivery, with clinical trials demonstrating improved in peptide-drug hybrids.

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