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Structural motif
Structural motif
Structural motif
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In a chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a common three-dimensional structure that appears in a variety of different, evolutionarily unrelated molecules.[1] A structural motif does not have to be associated with a sequence motif; it can be represented by different and completely unrelated sequences in different proteins or RNA.

In nucleic acids

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See also: Non-B database

Depending upon the sequence and other conditions, nucleic acids can form a variety of structural motifs which is thought to have biological significance.

Stem-loop
Stem-loop intramolecular base pairing is a pattern that can occur in single-stranded DNA or, more commonly, in RNA.[2] The structure is also known as a hairpin or hairpin loop. It occurs when two regions of the same strand, usually complementary in nucleotide sequence when read in opposite directions, base-pair to form a double helix that ends in an unpaired loop. The resulting structure is a key building block of many RNA secondary structures.
Cruciform DNA
Cruciform DNA is a form of non-B DNA that requires at least a 6 nucleotide sequence of inverted repeats to form a structure consisting of a stem, branch point and loop in the shape of a cruciform, stabilized by negative DNA supercoiling.[3] Two classes of cruciform DNA have been described; folded and unfolded.
G-quadruplex
G-quadruplex secondary structures (G4) are formed in nucleic acids by sequences that are rich in guanine.[4] They are helical in shape and contain guanine tetrads that can form from one,[5] two[6] or four strands.[7]
D-loop
A displacement loop or D-loop is a DNA structure where the two strands of a double-stranded DNA molecule are separated for a stretch and held apart by a third strand of DNA.[8] An R-loop is similar to a D-loop, but in this case the third strand is RNA rather than DNA.[9] The third strand has a base sequence which is complementary to one of the main strands and pairs with it, thus displacing the other complementary main strand in the region. Within that region the structure is thus a form of triple-stranded DNA. A diagram in the paper introducing the term illustrated the D-loop with a shape resembling a capital "D", where the displaced strand formed the loop of the "D".[10]

In proteins

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In proteins, a structural motif describes the connectivity between secondary structural elements. An individual motif usually consists of only a few elements, e.g., the 'helix-turn-helix' motif which has just three. Note that, while the spatial sequence of elements may be identical in all instances of a motif, they may be encoded in any order within the underlying gene. In addition to secondary structural elements, protein structural motifs often include loops of variable length and unspecified structure. Structural motifs may also appear as tandem repeats.

Beta hairpin
Extremely common. Two antiparallel beta strands connected by a tight turn of a few amino acids between them.
Greek key
Four beta strands, three connected by hairpins, the fourth folded over the top.
Omega loop
A loop in which the residues that make up the beginning and end of the loop are very close together.[11]
Helix-loop-helix
Consists of alpha helices bound by a looping stretch of amino acids. This motif is seen in transcription factors.
Zinc finger
Two beta strands with an alpha helix end folded over to bind a zinc ion. Important in DNA binding proteins.
Helix-turn-helix
Two α helices joined by a short strand of amino acids and found in many proteins that regulate gene expression.[12]
Nest
Extremely common. Three consecutive amino acid residues form an anion-binding concavity.[13]
Niche
Extremely common. Three or four consecutive amino acid residues form a cation-binding feature.[14]

See also

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References

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Further reading

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Structural motif

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from Grokipedia
A structural motif is a conserved three-dimensional arrangement of secondary structural elements in biomolecules, such as proteins and nucleic acids, that recurs across diverse sequences without direct evolutionary relatedness and often serves as a modular building block for larger functional architectures. In proteins, structural motifs typically consist of one or more secondary structure elements—like α-helices, β-strands, or loops—connected in specific geometries, forming supersecondary or tertiary patterns that can influence folding, stability, and interactions. Examples include the motif, common in DNA-binding proteins for sequence-specific recognition, and the beta-alpha-beta unit, a recurrent motif in nucleotide-binding enzymes like dehydrogenases. These motifs are smaller than domains but larger than individual secondary structures, enabling the prediction of protein function from atomic models in databases like the . In nucleic acids, particularly , structural motifs are recurrent folds involving base-pairing, stacking, and backbone conformations that stabilize secondary and tertiary structures, independent of primary sequence. Key examples encompass tetraloops (such as GNRA or UNCG types), which cap helical stems and mediate long-range interactions, and the kink-turn motif, which introduces sharp bends essential for assembly. These motifs underpin RNA's modular architecture, facilitating diverse roles in , , and molecular recognition. Overall, structural motifs highlight the principle of structural convergence in , where similar 3D folds arise from unrelated sequences to fulfill analogous functions, aiding in bioinformatics tools for motif detection, , and understanding biomolecular .

Overview and Fundamentals

Definition and Characteristics

A structural motif refers to a recurring three-dimensional (3D) arrangement of atoms, residues, or structural elements within biomolecules, such as proteins or nucleic acids, that appears across evolutionarily unrelated molecules despite lacking . These motifs are typically stabilized by non-covalent interactions, including hydrogen bonds, hydrophobic effects, and van der Waals forces, which enable the folding of disparate primary sequences into similar spatial configurations. Unlike larger structural domains, motifs often represent smaller, modular units that serve as fundamental building blocks in biomolecular architecture, such as compact features like beta turns or more extended patterns like beta hairpins. Key characteristics of structural motifs include their structural independence from primary sequence, allowing for where similar 3D folds emerge in proteins or RNAs with minimal shared ancestry. They play crucial roles in guiding biomolecular folding pathways and enabling functional properties, such as binding sites or catalytic regions, by providing stable points for higher-order assembly. For instance, motifs facilitate the transition from secondary structural elements (e.g., helices or sheets) to tertiary folds, often through supersecondary structures that combine multiple motifs into cooperative units. Structural motifs are distinct from sequence motifs, which are defined by specific patterns in the linear primary structure, such as conserved or sequences that may predict function but do not necessarily dictate 3D geometry. In contrast, structural motifs emphasize and can occur in molecules with divergent sequences, highlighting their reliance on physicochemical principles rather than genetic inheritance. Archetypal examples include the in proteins, a simple anti-parallel beta-sheet loop stabilized by hydrogen bonding, and the stem-loop in , a double-stranded capped by a single-stranded loop that aids in tertiary interactions.

Historical Development

The concept of structural motifs in proteins emerged in the through advancements in , which allowed researchers to visualize and classify recurring three-dimensional arrangements of secondary structures. Jane S. Richardson's seminal 1977 analysis of β-sheet topologies in known protein structures identified patterns such as parallel and antiparallel sheets, establishing these as fundamental motifs that reflect evolutionary relatedness among proteins. Her work, based on the limited but growing set of atomic-resolution structures available at the time, shifted focus from linear sequences to spatial architectures, laying the groundwork for motif-based classification in . In the 1980s, the recognition of structural motifs expanded to nucleic acids, particularly through crystallographic studies of (tRNA), where stem-loop hairpins were identified as conserved elements critical for folding and function. Additional tRNA structures solved during this decade, building on earlier low-resolution models, highlighted these motifs as modular units in RNA architecture. Concurrently, the (PDB), established in 1971, experienced exponential growth, reaching over 10,000 entries by 1999, which facilitated systematic motif detection across diverse biomolecules. Influential contributions included Alexander Rich's elucidation of alternative DNA conformations, such as left-handed in synthetic , which demonstrated motifs' role in DNA dynamics and regulation. Ada Yonath's pioneering crystallization of ribosomal subunits in 1980, culminating in high-resolution structures by the early 2000s, revealed intricate RNA and protein motifs within the , underscoring their functional interdependence. Post-2000 developments integrated (NMR) spectroscopy and (cryo-EM) to resolve motifs in larger, dynamic complexes previously inaccessible to methods. These techniques enabled the mapping of tertiary interactions and quaternary assemblies, enriching motif catalogs in the PDB. The understanding of motifs evolved from sequence-driven homology to structure-centric paradigms, revealing conserved folds amid sequence divergence and informing evolutionary models. The 2021 release of profoundly accelerated motif prediction by achieving near-experimental accuracy for protein structures, democratizing access via the AlphaFold Database and enabling motif annotation at scale. Between 2023 and 2025, AI advancements, including 3's multimodal predictions and generative models for , further propelled AI-driven motif databases, enhancing discovery of novel motifs in non-canonical biomolecules.

Structural Motifs in Nucleic Acids

Motifs in RNA Structures

RNA structural motifs are recurring three-dimensional folds that contribute to the functional versatility of RNA molecules, often forming through base pairing and tertiary interactions despite sequence variability. These motifs enable RNA to adopt compact architectures essential for roles in gene regulation, , and molecular recognition. In RNA, motifs like stem-loops and pseudoknots build secondary and tertiary structures, while elements such as kink-turns and A-minor motifs introduce bends and stabilize helices, facilitating dynamic conformational changes. The stem-loop, also known as the motif, is the most common secondary structure in , consisting of a double-stranded stem formed by Watson-Crick base pairing between complementary sequences and a single-stranded loop at the apex. This motif arises through intramolecular base pairing, typically involving A-U and G-C pairs in an A-form helix, with the loop size ranging from 3 to 8 nucleotides to minimize steric strain. Stem-loops are prevalent in microRNAs (miRNAs), where the characteristic structure is processed by to generate mature miRNAs that regulate via mRNA targeting. In , such as the from satellite tobacco ringspot virus, stem-loops form part of the catalytic core, positioning substrates for phosphodiester bond cleavage through reversible ligation. Pseudoknots represent a more complex motif involving stem-loops that create non-nested topologies, where a single-stranded pairs with a loop from another stem to form a second . This structure is stabilized by tertiary bonds, such as base triples (e.g., C+·(C-G)) and loop- interactions, which enhance thermal stability and compactness. Pseudoknots play a critical role in programmed ribosomal frameshifting, particularly -1 frameshifting in viruses, by acting as a mechanical barrier that pauses the over slippery sequences, allowing alternative ; for instance, the pseudoknot in (PLRV) achieves 15-20% frameshift efficiency to produce fusion proteins essential for replication. Beyond frameshifting, pseudoknots contribute to activity in the hepatitis delta virus (HDV) , where a nested forms the catalytic core for self-cleavage. Other notable RNA motifs include kink-turns and A-minor interactions, which modulate helical geometry and packing. The kink-turn (K-turn) is a recurrent motif comprising two helices connected by a three-nucleotide bulge and tandem sheared G·A base pairs, inducing a sharp ~120° bend in the RNA axis by juxtaposing minor grooves and widening the major groove. Structural parameters include C1′–C1′ distances of ~10.2 Å for canonical N1-class pairs and ~8.9 Å for tighter N3-class pairs, with the motif requiring Mg²⁺ ions or protein binding (e.g., L7Ae) for full folding. K-turns occur in ribosomal RNAs (e.g., Kt-7 in 23S rRNA) and spliceosomal U4 snRNA, facilitating compact folding. The A-minor motif involves the insertion of adenine's minor-groove edges from loops into the minor groove of adjacent A-form helices, forming hydrogen bonds with ribose 2′-OH groups of receptor base pairs, predominantly G-C steps. Classified into types I (multiple H-bonds) and II (single/double H-bonds), it stabilizes coaxial stacking of helices, as seen in 16S/23S rRNAs where 65% correlate with helix junctions, without altering groove widths but enhancing interhelical packing. These motifs underpin RNA's functional diversity, enabling and while exhibiting evolutionary conservation. In self-splicing introns, motifs like pseudoknots and kink-turns in group II introns (e.g., D6 branch ) position the bulged nucleophile for lariat formation, catalyzing excision via a two-metal-ion mechanism conserved from bacterial introns to eukaryotic spliceosomes. Regulatory roles include miRNA-mediated silencing via stem-loops and pseudoknot-driven frameshifting in viral genomes, allowing adaptive . Despite divergence, these motifs are evolutionarily conserved, as evidenced by shared catalytic cores (e.g., J5/6 linker in group II introns) across distant , underscoring RNA's ancient role in splicing and highlighting structural primacy over in function.

Motifs in DNA Structures

Structural motifs in DNA primarily manifest as deviations from the canonical right-handed B-form double helix, adopting stable three-dimensional configurations that influence genomic function. These non-B-form structures, such as cruciforms, G-quadruplexes, D-loops, and H-DNA, arise from specific sequence elements like inverted repeats or G-rich tracts and are often stabilized by negative supercoiling or environmental factors. Unlike the transient folds in RNA, DNA motifs tend to be more static and supercoil-dependent, playing roles in static genomic architecture rather than catalysis. Cruciform structures form X-shaped conformations from inverted repeat sequences in double-stranded DNA, where opposing strands each extrude an intra-strand hairpin, creating two paired arms. Extrusion occurs via two mechanisms in negatively supercoiled DNA: a concerted C-type pathway involving simultaneous arm formation or a stepwise S-type pathway with sequential hairpin development. Folded cruciforms feature base stacking within the hairpin stems for stability, while unfolded variants exhibit sharp bends at the four-way junction. Negative supercoiling significantly stabilizes these structures by relieving torsional stress. Cruciforms serve as models for Holliday junctions, facilitating homologous recombination by promoting strand exchange. G-quadruplexes (G4s) emerge from G-rich sequences, where two or more planar G-tetrads—each comprising four guanines linked by Hoogsteen hydrogen bonds—stack to form quadruplex helices stabilized by monovalent cations like potassium. These structures adopt diverse topologies, including parallel or antiparallel strands, and are prevalent in telomeres, where they cap chromosome ends, and in gene promoters, modulating oncogene expression. As of 2025, investigations highlight G4s as anticancer targets, with ligands disrupting their formation to inhibit tumor cell proliferation by inducing DNA damage and altering transcription, including recent progress on novel G4-stabilizing agents and their clinical potential. Other notable motifs include D-loops, H-DNA, and , which involve triple-helical arrangements or helical inversions. D-loops, or displacement loops, occur when a single-stranded DNA invades a duplex, displacing one strand to form a three-stranded intermediate, often during . H-DNA represents an intramolecular triplex in polypurine-polypyrimidine tracts with interruptions, where one strand folds back to bind via Hoogsteen pairing, yielding H-y ( motif) or H-p ( motif) conformations and leaving a single-stranded region. is a left-handed double-helical structure that forms preferentially in sequences with alternating s and s, such as CG repeats, under conditions of negative supercoiling or high salt concentrations; it features a zigzag backbone with alternating syn-anti conformations and dinucleotide repeat units. motifs are implicated in , , and immune responses, with anti-Z-DNA antibodies associated with autoimmune diseases like systemic . Structural metrics, such as propeller twist angles, distinguish these motifs; for instance, enhanced negative propeller twists in triplex regions reduce base-pair planarity and enhance groove accessibility compared to B-DNA's typical -5° to -15° range. These motifs exert profound biological influence, often impeding replication fork progression to cause pauses that heighten rates and genomic instability. In transcription, structures like H-DNA block , thereby repressing at specific loci. Evolutionarily, non-B DNA motifs drive genome diversification by promoting recombination hotspots and regulatory innovations, underscoring their significance in gene regulation across species.

Structural Motifs in Proteins

Secondary Structure Motifs

Secondary structure motifs in proteins are local, recurring patterns in the polypeptide backbone stabilized primarily by hydrogen bonds between backbone atoms, serving as fundamental building blocks for higher-order folds. These motifs include , , and turns, which collectively enable the protein chain to adopt compact, functional conformations despite sequence variability. The is a right-handed coiled structure in which the polypeptide backbone forms a cylinder with approximately 3.6 residues per turn and a pitch of 5.4 . It is stabilized by intramolecular hydrogen bonds between the carbonyl oxygen of residue i and the hydrogen of residue i+4, creating a regular pattern along the helix axis. The characteristic backbone dihedral angles are φ ≈ -60° and ψ ≈ -45°, positioning these residues in a favored region of the . In membrane proteins, alpha helices often exhibit amphipathic character, with hydrophobic residues facing the and hydrophilic ones oriented toward the aqueous environment or protein interior. Beta sheets consist of two or more beta strands—extended polypeptide segments with φ ≈ -120° and ψ ≈ +120°—aligned either parallel or antiparallel to form a pleated surface stabilized by interstrand bonds between carbonyl oxygens and hydrogens. Antiparallel sheets feature more linear hydrogen bonding patterns, while sheets have slightly offset bonds, contributing to overall stability. All observed beta sheets display a right-handed twist, typically around 10–20° per residue, arising from the intrinsic of L-amino acids and optimizing side-chain packing. A common motif within beta sheets is the , formed by two adjacent antiparallel strands connected by a short turn of 2–5 residues, allowing the chain to reverse direction compactly. Turns and loops connect secondary structure elements, with beta turns being the most prevalent type for reversing chain direction over four consecutive residues. Classified into types I, II, II', and I' based on dihedral angles and ing patterns (e.g., type I features a between residues i and i+3 with specific φ/ψ values for positions i+1 and i+2), these turns accommodate diverse side chains while maintaining backbone flexibility. Type IV turns, lacking a standard i to i+3 , provide additional variability. Loops, often unstructured, link distant elements but contribute to functional sites. In globular proteins, secondary structure motifs account for approximately 50% of residues, with the remainder in loops or irregular regions; this prevalence is assessed through Ramachandran plots, which map allowed φ/ψ angles and highlight secondary structure clusters./01:_Unit_I-_Structure_and_Catalysis/04:_The_Three-Dimensional_Structure_of_Proteins/4.02:_Secondary_Structure_and_Loops)

Tertiary and Quaternary Motifs

Tertiary structural motifs in proteins represent compact, three-dimensional folds that integrate multiple secondary structural elements to form functional units, often enabling specific interactions such as binding or enzymatic activity. These motifs extend beyond local secondary structures by incorporating spatial arrangements that stabilize higher-order architectures, frequently involving hydrophobic cores, hydrogen bonding networks, and sometimes metal ion coordination. In contrast to isolated alpha helices or beta sheets, tertiary motifs like the and exemplify how proteins achieve precise recognition of macromolecules such as DNA. The (HTH) motif consists of two connected by a short turn of three to four , forming a recognition that inserts into the major groove of for sequence-specific binding. This motif is stabilized by hydrophobic interactions between the helices and often operates as part of a three- bundle, where the second helix makes direct contacts with DNA bases via side-chain atoms. A classic example is the lambda repressor protein from bacteriophage lambda, where the HTH motif binds to operator sequences (O_L1), regulating viral through lock-and-key complementarity and induced fit mechanisms. Zinc finger motifs, particularly the C2H2 subtype, feature a compact beta-beta-alpha fold coordinated by a zinc ion bound to two cysteine and two histidine residues, creating a stable domain approximately 25-30 amino acids long. The zinc stabilizes a short beta hairpin followed by an alpha helix, with the helix presenting key residues (often at positions -1, 2, 3, and 6 relative to the helix) that contact three to four DNA base pairs in the major groove. This modular architecture allows tandem arrays of C2H2 fingers to recognize extended DNA sequences (20-40 base pairs), facilitating RNA binding in some cases, as seen in transcription factors like CTCF that regulate chromatin boundaries. Among other tertiary motifs, the Greek key represents a topological of four antiparallel beta strands connected by a characteristic crossover loop, forming of many beta-barrels and beta-sandwiches. This motif, often left-handed in beta-barrels with five or six strands, enforces specific folding constraints and is prevalent in half of analyzed beta-barrel structures, contributing to protein stability through edge-to-edge strand packing. The omega loop, a nonregular secondary structure, appears as a surface-exposed segment of 6-16 residues lacking regular dihedral angles but rich in bonds, adopting a loop shape that remains flexible yet functionally critical. These loops often act as lids over active sites, enabling substrate access in enzymes and molecular recognition in binding proteins. Nest and niche motifs provide small, precise sites for binding within tertiary folds, utilizing main-chain carbonyl or groups from residue triads or tetrads. A nest, typically a three-residue motif, binds anions like phosphates via bridging NH atoms from positions i and i+2, commonly found in Schellman loops and iron-sulfur clusters. In contrast, niches—such as the three-residue niche3 (with alpha-beta conformation at i+2 and i+3) or four-residue niche4 (alpha-alpha-beta at i+2 to i+4)—accommodate cations like Na+, +, or Ca2+ through carbonyl oxygens, occurring in about 7% of soluble protein residues and often at beta-turns or alpha-helix C-termini to support in enzymes like the Na+/+-. Quaternary motifs extend tertiary elements across subunit interfaces, promoting multimer assembly and functional regulation. The , a hallmark of basic region-leucine zipper (bZIP) transcription factors, forms a coiled-coil dimer via alpha helices with residues at the d positions of a heptad repeat, stabilized by hydrophobic knobs-into-holes packing and electrostatic interactions at e and g positions. This motif drives reversible homodimerization or heterodimerization (e.g., Fos-Jun pairs), enabling over 1,400 potential dimers among human bZIPs and facilitating DNA binding through allosteric coupling that induces basic region helix formation. In assemblies like GCN4, the zipper supports short-lived dimers (<1 second lifetime) essential for transcriptional regulation and higher-order complex formation.

Motifs in Other Biomolecules

In Carbohydrates

In carbohydrates, structural motifs primarily arise from the arrangement of monosaccharide units linked by glycosidic bonds, which dictate the overall three-dimensional conformation of polysaccharides and glycoconjugates. The α-1,4-glycosidic linkage, as seen in amylose, a component of , promotes a left-handed helical structure with approximately six glucose units per turn, facilitating compact packing and enzymatic accessibility for energy storage. In contrast, the β-1,4-glycosidic linkage in cellulose results in extended, linear chains that form rigid, hydrogen-bonded microfibrils, providing tensile strength in plant cell walls. These linkage-specific motifs influence solubility, digestibility, and biological roles, with α-linkages generally yielding more flexible, soluble polymers compared to the insoluble β-forms. Branching motifs further diversify carbohydrate structures, particularly in complex glycans attached to proteins. Glycoclusters, multivalent arrays of glycan units, and antennae—the branched extensions in N-linked glycoproteins—create spatial arrangements that enhance avidity in molecular recognition. At the monosaccharide level, the predominant chair conformation (⁴C₁ for D-glucopyranose) minimizes steric hindrance, positioning hydroxyl groups equatorially for optimal hydrogen bonding and linkage formation. These motifs, often biantennary or triantennary in glycoproteins, contribute to conformational flexibility and surface display on cells. Specific examples illustrate how modifications enhance functional motifs. In heparin, a sulfated glycosaminoglycan, distinct sulfation patterns—such as 3-O-sulfation at glucosamine residues—form binding motifs that selectively interact with proteins like antithrombin III, regulating coagulation. Similarly, glycan folds recognized by lectins, such as the β-sandwich domains in galectins binding β-galactoside motifs, mediate cell adhesion and signaling through precise stereochemical complementarity. Structural analysis of these motifs relies on advanced techniques to resolve torsion angles and dynamics. Nuclear magnetic resonance (NMR) spectroscopy determines glycosidic torsion angles φ (H1'-C1'-O-Cn) and ψ (C1'-O-Cn-Hn), revealing preferred conformations like the ⁴C₁ chair with exoanomeric effects stabilizing linkages. These motifs play critical roles in recognition, as in blood group antigens where ABO-specific terminal glycans (e.g., α-GalNAc for A antigen) serve as motifs for antibody binding and transfusion compatibility. Post-2023 cryo-electron microscopy (cryo-EM) studies have provided insights into glycan shields on viruses, such as the densely branched N-glycans on SARS-CoV-2 spike protein forming a protective lattice that modulates immune evasion and antibody access.

In Lipids and Membranes

In lipid bilayers, a fundamental structural motif is the lamellar phase, where amphiphilic lipids self-assemble into stacked sheets with hydrophobic tails oriented inward and hydrophilic headgroups facing aqueous environments on both sides. This arrangement minimizes exposure of nonpolar regions to water, forming a bilayer thickness typically around 4-5 nm for common phospholipids like phosphatidylcholine. The stability of this motif arises from van der Waals interactions between tails and electrostatic repulsion between headgroups, as detailed in structural studies of hydrated bilayers. Within these lamellae, specialized domains such as lipid rafts emerge as cholesterol- and sphingolipid-enriched motifs, creating liquid-ordered phases that differ from the surrounding liquid-disordered regions due to tighter packing and reduced fluidity. These rafts, often 10-200 nm in size, facilitate lateral segregation and are implicated in membrane organization. Lipid shapes dictate alternative motifs beyond bilayers, governed by the packing parameter P=Va⋅lP = \frac{V}{a \cdot l}, where VV is the hydrophobic tail volume, aa the headgroup area, and ll the tail length. Cylindrical s with P≈1P \approx 1 favor lamellar bilayers or micelles, while conical shapes with P>1P > 1 promote inverted hexagonal phases (H_{II}), featuring lipid cylinders with heads outward and water channels inside. These non-lamellar motifs are critical for fusion events, as the negative curvature of H_{II} phases lowers the energy barrier for stalk formation between fusing bilayers. Inverted micelles (P > 1) form in apolar environments, with headgroups facing inward to enclose an aqueous core and tails interacting with the nonpolar solvent. Specific lipid motifs include clusters in mitochondrial membranes, where this diphosphatidylglycerol forms oligomeric assemblies that stabilize high-curvature regions like cristae, comprising up to 20% of inner membrane lipids. Lipid rafts often incorporate (GPI)-anchored lipids, enhancing domain rigidity through saturated acyl chains that align with . Recent cryo-EM studies as of 2025 have resolved lipid motifs around membrane-embedded proteins, revealing clusters binding via specific pockets in pores and scaffolds, with densities indicating dynamic interactions at 3-4 Å resolution. Functionally, these motifs support signaling, as seen with (PIP2) headgroups clustering to recruit effectors in plasma membranes, and contribute to curvature by lipids like promoting hexagonal transitions that aid fusion without protein involvement. motifs similarly influence mitochondrial dynamics through curvature stabilization.

Identification and Applications

Computational Methods

Computational methods for detecting and predicting structural motifs in biomolecules rely on algorithms that analyze three-dimensional structures, often drawing from large databases of experimentally determined conformations. These approaches address the challenge of identifying recurring patterns across diverse sequences, enabling the of motifs in proteins, nucleic acids, and other biomolecules. Template-based and fragment-based detection methods form the core of motif identification, while predictive tools leverage to infer motifs de novo. Template-based search methods, such as the Dali server, facilitate the detection of structural motifs by performing 3D alignments between a query structure and entries in the (PDB). The Dali server compares protein structures using distance-matrix alignment, identifying similarities that reveal conserved motifs even among distantly related sequences. This tool is particularly effective for unifying protein families and detecting motifs like helices or beta-sheets through global or local superimpositions. Fragment-based approaches complement this by focusing on partial matches, allowing detection of motifs within larger, non-homologous structures. For instance, DeepFold employs deep convolutional neural networks to learn low-dimensional representations of structural fragments, enabling efficient retrieval and classification of motifs such as zinc fingers or leucine zippers from protein databases. Prediction of structural motifs has advanced significantly with models that generate atomic-level structures from sequences. AlphaFold3, released in 2024, predicts multi-molecule complexes including proteins, nucleic acids, and ligands, thereby inferring motifs like DNA-binding domains or hairpins through end-to-end diffusion-based modeling. For secondary structures, RNAfold uses dynamic programming to compute minimum free-energy folds, identifying common motifs such as stem-loops or pseudoknots based on thermodynamic parameters. In glycans, post-2023 predictors like CandyCrunch apply to data, reconstructing glycan trees and motifs with up to 90% accuracy in top-ranked predictions, addressing the branching complexity unique to carbohydrates. Key databases underpin these methods by providing curated repositories of motifs. For proteins, and CATH classify domains hierarchically into classes, architectures, topologies, and superfamilies, facilitating motif searches based on evolutionary relationships. RNA STRAND compiles validated secondary structures from diverse RNA types, enabling statistical analysis of motifs across organisms. The PDB serves as a central archive for all biomolecular structures, where motif similarity is quantified using root-mean-square deviation (RMSD), with thresholds below 2 indicating high structural conservation. Challenges in computational motif detection include accommodating structural flexibility, particularly in loops and disordered regions that deviate from rigid templates. Machine learning advances, such as 2025 diffusion models for membrane proteins, are addressing this by generating ensemble predictions that capture lipid-induced conformations and motifs in dynamic environments like bilayers.

Biological and Therapeutic Importance

Structural motifs play crucial roles in biological specificity, particularly in protein-DNA interactions. Zinc finger motifs, for instance, are essential for transcription factors that bind specific DNA sequences to regulate gene expression, enabling precise control over cellular processes such as development and response to environmental signals. These motifs exemplify how recurrent structural elements confer functional modularity, allowing proteins to interact with diverse targets while maintaining stability. Evolutionary modularity is a key feature of structural motifs across biomolecules, where they act as reusable building blocks that facilitate and functional . In protein , motifs enable the recombination of domains, promoting evolvability by allowing incremental changes without disrupting overall . This is evident in the conservation of motifs like beta-sheets and helices, which support diverse functions from to signaling, underscoring their role in the diversification of biomolecular systems. However, disruptions in motif folding can lead to diseases; in prion disorders, misfolded alpha-helical motifs convert to beta-sheet-rich conformations, propagating aggregates that cause neurodegeneration. Therapeutically, structural motifs serve as targets for drug design, enhancing selectivity and efficacy. G-quadruplex motifs in DNA and RNA oncogenes are stabilized by small molecules like CX-5461 (Pidnarulex), which inhibits RNA polymerase I and induces DNA damage in cancer cells, earning FDA Fast Track Designation for advanced solid tumors. In vaccine development, glycan motifs on the SARS-CoV-2 spike protein are manipulated to improve immunogenicity; glycan-masked receptor-binding domain vaccines elicit broader neutralizing antibodies by shielding non-neutralizing epitopes and exposing conserved sites. Protein engineering leverages motifs for de novo design, using tools like to create custom structures with predefined folds, such as novel binders or enzymes, by assembling secondary structure motifs into stable scaffolds. In gene editing, CRISPR-Cas9 relies on protospacer-adjacent motif (PAM) recognition for target specificity, where the NGG sequence adjacent to the guide RNA directs cleavage, enabling precise genomic modifications. Emerging applications in 2025 integrate AI with motif analysis for diagnostics, where models predict protein and structural motifs to identify disease-associated variants, accelerating discovery in and infectious diseases. In synthetic biology, motifs drive interdisciplinary innovations, such as designing artificial protein complexes that mimic natural assemblies for biosensors or therapeutic delivery systems.

References

  1. https://pmc.ncbi.nlm.nih.gov/articles/PMC5513761/
  2. http://compbio.berkeley.edu/people/brenner/pubs/hendrix-2005-qrb-rnamotif.pdf
  3. https://www.pnas.org/doi/10.1073/pnas.0704594104
  4. https://pmc.ncbi.nlm.nih.gov/articles/PMC7746303/
  5. https://www.annualreviews.org/content/journals/10.1146/annurev.biochem.68.1.287
  6. https://onlinelibrary.wiley.com/doi/abs/10.1002/9780470015902.a0003132.pub2
  7. https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/protein-structural-motifs
  8. https://www.nature.com/articles/268495a0
  9. https://www.jbc.org/article/S0021-9258%2820%2985846-3/fulltext
  10. https://www.sciencedirect.com/science/article/pii/S0021925821003331
  11. https://pmc.ncbi.nlm.nih.gov/articles/PMC102472/
  12. https://pmc.ncbi.nlm.nih.gov/articles/PMC2791029/
  13. https://www.sciencedirect.com/science/article/pii/S0092867409014536
  14. https://www.cell.com/structure/fulltext/S0969-2126%2824%2900331-9
  15. https://www.sciencedirect.com/science/article/pii/S258900422500272X
  16. https://www.pnas.org/doi/10.1073/pnas.2315002121
  17. https://www.nature.com/articles/s41598-024-69021-2
  18. https://pmc.ncbi.nlm.nih.gov/articles/PMC7656661/
  19. https://www.sciencedirect.com/science/article/pii/S1046202316300743
  20. https://www.annualreviews.org/doi/pdf/10.1146/annurev.physchem.59.032607.093743
  21. https://www.sciencedirect.com/science/article/abs/pii/S0022283600935605
  22. https://pmc.ncbi.nlm.nih.gov/articles/PMC2670756/
  23. https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.0030213
  24. https://www.cambridge.org/core/journals/quarterly-reviews-of-biophysics/article/kinkturn-in-the-structural-biology-of-rna/2FF540BF0B3D602596FC4BD9CA6CD9B8
  25. https://pmc.ncbi.nlm.nih.gov/articles/PMC149158/
  26. https://rnajournal.cshlp.org/content/14/12/2465.full
  27. https://www.nature.com/articles/s41586-023-06746-6
  28. https://pmc.ncbi.nlm.nih.gov/articles/PMC5014005/
  29. https://pmc.ncbi.nlm.nih.gov/articles/PMC3176155/
  30. https://pmc.ncbi.nlm.nih.gov/articles/PMC5295012/
  31. https://pmc.ncbi.nlm.nih.gov/articles/PMC9180970/
  32. https://pmc.ncbi.nlm.nih.gov/articles/PMC306521/
  33. https://pmc.ncbi.nlm.nih.gov/articles/PMC1303095/
  34. https://pmc.ncbi.nlm.nih.gov/articles/PMC555056/
  35. https://pubmed.ncbi.nlm.nih.gov/9653031/
  36. https://pmc.ncbi.nlm.nih.gov/articles/PMC12347789/
  37. https://pmc.ncbi.nlm.nih.gov/articles/PMC12109316/
  38. https://pmc.ncbi.nlm.nih.gov/articles/PMC11314571/
  39. https://pmc.ncbi.nlm.nih.gov/articles/PMC12029830/
  40. https://pmc.ncbi.nlm.nih.gov/articles/PMC6532985/
  41. https://pmc.ncbi.nlm.nih.gov/articles/PMC11667243/
  42. https://pmc.ncbi.nlm.nih.gov/articles/PMC2586808/
  43. https://www.cell.com/trends/biochemical-sciences/fulltext/S0968-0004(25)00001-5
  44. https://pmc.ncbi.nlm.nih.gov/articles/PMC8867553/
  45. https://pmc.ncbi.nlm.nih.gov/articles/PMC4538819/
  46. https://pmc.ncbi.nlm.nih.gov/articles/PMC9877202/
  47. https://www.pnas.org/doi/10.1073/pnas.37.4.205
  48. https://pmc.ncbi.nlm.nih.gov/articles/PMC2034331/
  49. https://www.sciencedirect.com/science/article/pii/0022283682901632
  50. https://onlinelibrary.wiley.com/doi/abs/10.1002/pro.4020
  51. https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/helix-turn-helix
  52. https://www.sciencedirect.com/science/article/pii/B9780128176443000052
  53. https://pubmed.ncbi.nlm.nih.gov/8144673/
  54. https://pmc.ncbi.nlm.nih.gov/articles/PMC5509000/
  55. https://doi.org/10.1016/j.str.2003.09.015
  56. https://pubmed.ncbi.nlm.nih.gov/10861931/
  57. https://pubmed.ncbi.nlm.nih.gov/7601335/
  58. https://www.sciencedirect.com/science/article/abs/pii/S0022283608014265
  59. https://doi.org/10.1016/j.jmb.2008.11.007
  60. https://pmc.ncbi.nlm.nih.gov/articles/PMC2800128/
  61. https://doi.org/10.2174/138920309788452164
  62. https://www.sciencedirect.com/topics/neuroscience/amylose
  63. https://bio.libretexts.org/Courses/Roosevelt_University/BCHM_355_455_Biochemistry_%28Roosevelt_University%29/09%253A_Carbohydrates/9.03%253A_Polysaccharides
  64. https://pubs.acs.org/doi/10.1021/acs.jctc.4c00543
  65. https://pubs.acs.org/doi/10.1021/acs.analchem.7b04293
  66. https://www.ncbi.nlm.nih.gov/books/NBK579981/
  67. https://www.sciencedirect.com/science/article/pii/S0092867407003157
  68. https://www.science.org/doi/10.1126/sciadv.abl6026
  69. https://www.ncbi.nlm.nih.gov/books/NBK1943/
  70. https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202304047
  71. https://www.ncbi.nlm.nih.gov/books/NBK579929/
  72. https://academic.oup.com/nsr/article/11/7/nwae206/7693733
  73. https://pmc.ncbi.nlm.nih.gov/articles/PMC2747654/
  74. https://pmc.ncbi.nlm.nih.gov/articles/PMC6196108/
  75. https://pmc.ncbi.nlm.nih.gov/articles/PMC50827/
  76. https://pmc.ncbi.nlm.nih.gov/articles/PMC3220359/
  77. https://pmc.ncbi.nlm.nih.gov/articles/PMC2757492/
  78. https://www.nature.com/articles/s41467-025-58334-z
  79. https://pmc.ncbi.nlm.nih.gov/articles/PMC9704524/
  80. https://pmc.ncbi.nlm.nih.gov/articles/PMC8310398/
  81. https://biomarkerres.biomedcentral.com/articles/10.1186/s40364-021-00345-1
  82. https://pmc.ncbi.nlm.nih.gov/articles/PMC353226/
  83. https://royalsocietypublishing.org/doi/10.1098/rspb.2012.2863
  84. https://www.pnas.org/doi/10.1073/pnas.2019631118
  85. https://pmc.ncbi.nlm.nih.gov/articles/PMC12007140/
  86. https://pmc.ncbi.nlm.nih.gov/articles/PMC11460674/
  87. https://www.nature.com/articles/s41586-023-06415-8
  88. https://www.idtdna.com/page/support-and-education/decoded-plus/importance-of-the-pam-sequences-in-crispr-cas9-gene-editing/
  89. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1498662/full
  90. https://pmc.ncbi.nlm.nih.gov/articles/PMC5899735/
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