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Structural motif

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.^[1]^[2] 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.^[1] Examples include the helix-turn-helix 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 Protein Data Bank.^[1] In nucleic acids, particularly RNA, structural motifs are recurrent folds involving base-pairing, stacking, and backbone conformations that stabilize secondary and tertiary structures, independent of primary sequence.^[2] 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 ribosomal RNA assembly.^[2] These motifs underpin RNA's modular architecture, facilitating diverse roles in catalysis, regulation, and molecular recognition.^[2] Overall, structural motifs highlight the principle of structural convergence in biology, where similar 3D folds arise from unrelated sequences to fulfill analogous functions, aiding in bioinformatics tools for motif detection, protein engineering, and understanding biomolecular evolution.^[1]^[2]

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 sequence homology.^[1] 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.^[3] 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.^[4] Key characteristics of structural motifs include their structural independence from primary sequence, allowing for convergent evolution where similar 3D folds emerge in proteins or RNAs with minimal shared ancestry.^[5] They play crucial roles in guiding biomolecular folding pathways and enabling functional properties, such as binding sites or catalytic regions, by providing stable nucleation points for higher-order assembly.^[6] 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.^[1] Structural motifs are distinct from sequence motifs, which are defined by specific patterns in the linear primary structure, such as conserved amino acid or nucleotide sequences that may predict function but do not necessarily dictate 3D geometry.^[7] In contrast, structural motifs emphasize spatial organization and can occur in molecules with divergent sequences, highlighting their reliance on physicochemical principles rather than genetic inheritance. Archetypal examples include the beta hairpin in proteins, a simple anti-parallel beta-sheet loop stabilized by hydrogen bonding, and the stem-loop in RNA, a double-stranded helix capped by a single-stranded loop that aids in tertiary interactions.^[4]

Historical Development

The concept of structural motifs in proteins emerged in the 1970s through advancements in X-ray crystallography, 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.^[8] 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 structural biology.^[9] In the 1980s, the recognition of structural motifs expanded to nucleic acids, particularly through crystallographic studies of transfer RNA (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.^[10] Concurrently, the Protein Data Bank (PDB), established in 1971, experienced exponential growth, reaching over 10,000 entries by 1999, which facilitated systematic motif detection across diverse biomolecules.^[11] Influential contributions included Alexander Rich's elucidation of alternative DNA conformations, such as left-handed Z-DNA in synthetic oligonucleotides, which demonstrated motifs' role in DNA dynamics and regulation.^[12] 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 ribosome, underscoring their functional interdependence.^[13] Post-2000 developments integrated nuclear magnetic resonance (NMR) spectroscopy and cryogenic electron microscopy (cryo-EM) to resolve motifs in larger, dynamic complexes previously inaccessible to X-ray methods. These techniques enabled the mapping of tertiary interactions and quaternary assemblies, enriching motif catalogs in the PDB.^[14] The understanding of motifs evolved from sequence-driven homology to structure-centric paradigms, revealing conserved folds amid sequence divergence and informing evolutionary models.^[15] The 2021 release of AlphaFold profoundly accelerated motif prediction by achieving near-experimental accuracy for protein structures, democratizing access via the AlphaFold Database and enabling motif annotation at scale.^[16] Between 2023 and 2025, AI advancements, including AlphaFold 3's multimodal predictions and generative models for structural biology, further propelled AI-driven motif databases, enhancing discovery of novel motifs in non-canonical biomolecules.^[17]

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, catalysis, 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.^[18] The stem-loop, also known as the hairpin motif, is the most common secondary structure in RNA, 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 hairpin structure is processed by Dicer to generate mature miRNAs that regulate gene expression via mRNA targeting. In ribozymes, such as the hairpin ribozyme from satellite tobacco ringspot virus, stem-loops form part of the catalytic core, positioning substrates for phosphodiester bond cleavage through reversible ligation.^[18]^[19]^[20]^[21] Pseudoknots represent a more complex motif involving interlocking stem-loops that create non-nested topologies, where a single-stranded region pairs with a loop from another stem to form a second helix. This structure is stabilized by tertiary hydrogen bonds, such as base triples (e.g., C+·(C-G)) and loop-helix 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 ribosome over slippery sequences, allowing alternative reading frame translation; for instance, the pseudoknot in potato leafroll virus (PLRV) achieves 15-20% frameshift efficiency to produce fusion proteins essential for replication. Beyond frameshifting, pseudoknots contribute to ribozyme activity in the hepatitis delta virus (HDV) ribozyme, where a nested pseudoknot forms the catalytic core for self-cleavage.^[22]^[23]^[22] 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.^[24]^[25]^[26]^[26] These motifs underpin RNA's functional diversity, enabling catalysis and regulation while exhibiting evolutionary conservation. In self-splicing introns, motifs like pseudoknots and kink-turns in group II introns (e.g., D6 branch helix) position the bulged adenosine 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 gene expression. Despite sequence divergence, these motifs are evolutionarily conserved, as evidenced by shared catalytic cores (e.g., J5/6 linker in group II introns) across distant species, underscoring RNA's ancient role in splicing and highlighting structural primacy over sequence in function.^[27]^[27]^[28]^[28]

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.^[29]^[30] 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.^[31] 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.^[32] Folded cruciforms feature base stacking within the hairpin stems for stability, while unfolded variants exhibit sharp bends at the four-way junction.^[33] Negative supercoiling significantly stabilizes these structures by relieving torsional stress.^[34] Cruciforms serve as models for Holliday junctions, facilitating homologous recombination by promoting strand exchange.^[35] 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.^[36] 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.^[37] 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.^[38]^[39] Other notable motifs include D-loops, H-DNA, and Z-DNA, 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 homologous recombination.^[40] H-DNA represents an intramolecular triplex in polypurine-polypyrimidine tracts with pyrimidine interruptions, where one strand folds back to bind via Hoogsteen pairing, yielding H-y (pyrimidine motif) or H-p (purine motif) conformations and leaving a single-stranded region.^[41]^[42] Z-DNA is a left-handed double-helical structure that forms preferentially in sequences with alternating purines and pyrimidines, such as CG repeats, under conditions of negative supercoiling or high salt concentrations; it features a zigzag phosphate backbone with alternating syn-anti glycosidic bond conformations and dinucleotide repeat units. Z-DNA motifs are implicated in transcriptional regulation, DNA repair, and immune responses, with anti-Z-DNA antibodies associated with autoimmune diseases like systemic lupus erythematosus.^[43] 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.^[44] These motifs exert profound biological influence, often impeding replication fork progression to cause pauses that heighten mutation rates and genomic instability.^[30] In transcription, structures like H-DNA block RNA polymerase, thereby repressing gene expression at specific loci.^[45] Evolutionarily, non-B DNA motifs drive genome diversification by promoting recombination hotspots and regulatory innovations, underscoring their significance in gene regulation across species.^[46]

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 alpha helices, beta sheets, and turns, which collectively enable the protein chain to adopt compact, functional conformations despite sequence variability.^[47] The alpha helix is a right-handed coiled structure in which the polypeptide backbone forms a cylinder with approximately 3.6 amino acid residues per turn and a pitch of 5.4 Å.^[47] It is stabilized by intramolecular hydrogen bonds between the carbonyl oxygen of residue i and the amide hydrogen of residue i+4, creating a regular pattern along the helix axis.^[47] The characteristic backbone dihedral angles are φ ≈ -60° and ψ ≈ -45°, positioning these residues in a favored region of the Ramachandran plot. In membrane proteins, alpha helices often exhibit amphipathic character, with hydrophobic residues facing the lipid bilayer and hydrophilic ones oriented toward the aqueous environment or protein interior.^[48] 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 hydrogen bonds between carbonyl oxygens and amide hydrogens. Antiparallel sheets feature more linear hydrogen bonding patterns, while parallel 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 asymmetry of L-amino acids and optimizing side-chain packing.^[49] A common motif within beta sheets is the beta hairpin, formed by two adjacent antiparallel strands connected by a short turn of 2–5 residues, allowing the chain to reverse direction compactly.^[50] 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 hydrogen bonding patterns (e.g., type I features a hydrogen bond 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 hydrogen bond, 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 ligand 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 helix-turn-helix and zinc finger exemplify how proteins achieve precise recognition of macromolecules such as DNA.^[51] The helix-turn-helix (HTH) motif consists of two alpha helices connected by a short turn of three to four amino acids, forming a recognition helix that inserts into the major groove of DNA for sequence-specific binding. This motif is stabilized by hydrophobic interactions between the helices and often operates as part of a three-helix 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 gene expression through lock-and-key complementarity and induced fit mechanisms.^[51]^[52]^[53] 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.^[54]^[55] Among other tertiary motifs, the Greek key represents a topological pattern of four antiparallel beta strands connected by a characteristic crossover loop, forming the core 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 hydrogen 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.^[56]^[57] Nest and niche motifs provide small, precise sites for ion binding within tertiary folds, utilizing main-chain carbonyl or amide 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+, K+, 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 ion transport in enzymes like the Na+/K+-ATPase.^[58]^[59] Quaternary motifs extend tertiary elements across subunit interfaces, promoting multimer assembly and functional regulation. The leucine zipper, a hallmark of basic region-leucine zipper (bZIP) transcription factors, forms a coiled-coil dimer via alpha helices with leucine 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.^[60]^[61]

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 starch, promotes a left-handed helical structure with approximately six glucose units per turn, facilitating compact packing and enzymatic accessibility for energy storage.^[62] 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.^[63] 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.^[64] 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.^[65] 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.^[66] These motifs, often biantennary or triantennary in glycoproteins, contribute to conformational flexibility and surface display on cells.^[67] 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.^[68] 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.^[69] 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.^[70] 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.^[71] 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.^[72]

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.^[73]^[74] Lipid shapes dictate alternative motifs beyond bilayers, governed by the packing parameter P = \frac{V}{a \cdot l}, where V is the hydrophobic tail volume, a the headgroup area, and l the tail length. Cylindrical lipids with P \approx 1 favor lamellar bilayers or micelles, while conical shapes with P > 1 promote inverted hexagonal phases (H_{II}), featuring lipid cylinders with heads outward and water channels inside. These non-lamellar motifs are critical for membrane 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.^[75]^[76] Specific lipid motifs include cardiolipin 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 glycosylphosphatidylinositol (GPI)-anchored lipids, enhancing domain rigidity through saturated acyl chains that align with cholesterol. Recent cryo-EM studies as of 2025 have resolved lipid motifs around membrane-embedded proteins, revealing cholesterol 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 phosphatidylinositol 4,5-bisphosphate (PIP2) headgroups clustering to recruit effectors in plasma membranes, and contribute to curvature by lipids like phosphatidylethanolamine promoting hexagonal transitions that aid fusion without protein involvement. Cardiolipin motifs similarly influence mitochondrial dynamics through curvature stabilization.^[77]^[78]^[79]

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 classification 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 machine learning 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 Protein Data Bank (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 machine learning 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 RNA hairpins through end-to-end diffusion-based modeling. For RNA 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 deep learning to tandem mass spectrometry 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, SCOP 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 Å 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.^[80] These motifs exemplify how recurrent structural elements confer functional modularity, allowing proteins to interact with diverse targets while maintaining stability.^[81] Evolutionary modularity is a key feature of structural motifs across biomolecules, where they act as reusable building blocks that facilitate adaptation and functional innovation. In protein evolution, motifs enable the recombination of domains, promoting evolvability by allowing incremental changes without disrupting overall structure.^[82] This modularity is evident in the conservation of motifs like beta-sheets and helices, which support diverse functions from catalysis to signaling, underscoring their role in the diversification of biomolecular systems.^[83] 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.^[84] 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.^[85] 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.^[86] Protein engineering leverages motifs for de novo design, using tools like Rosetta to create custom structures with predefined folds, such as novel binders or enzymes, by assembling secondary structure motifs into stable scaffolds.^[87] 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.^[88] Emerging applications in 2025 integrate AI with motif analysis for diagnostics, where deep learning models predict protein and RNA structural motifs to identify disease-associated variants, accelerating biomarker discovery in oncology and infectious diseases.^[89] In synthetic biology, motifs drive interdisciplinary innovations, such as designing artificial protein complexes that mimic natural assemblies for biosensors or therapeutic delivery systems.^[90]

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A minimal hairpin ribozyme contains four base-paired helices, H1 through H4, and two unpaired loops, A and B, with the reactive phosphodiester located within ...Missing: miRNA paper
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Frameshifting RNA pseudoknots: Structure and mechanism - PMC
The subject of this review is RNA pseudoknots and related RNA motifs that simulate −1 programmed ribosomal frameshifting (−1 PRF). An important goal of these ...Missing: interlocking paper
[23]
Pseudoknots: RNA Structures with Diverse Functions | PLOS Biology
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The kink-turn in the structural biology of RNA
Apr 12, 2018 · The k-turn is a common structural motif in many functional RNA species, that introduces a sharp bend into the axis of duplex RNA.
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The kink-turn: a new RNA secondary structure motif - PMC - NIH
This helix–internal loop–helix motif has an unusual conformation, which includes a kink in its phosphodiester backbone that bends the RNA helix axis by ∼120°.Missing: review | Show results with:review
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Annotation of tertiary interactions in RNA structures reveals variations and correlations
### Summary of A-minor Motif in RNA Structures
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Structural insights into intron catalysis and dynamics during splicing
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RNA structure in splicing: An evolutionary perspective - PMC - NIH
RNA structure replaces the need for essential factors in splicing. In our recent report published in Genome Research,56 we identified evolutionarily conserved ...
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Cruciform structures are a common DNA feature important for ...
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Effects of Replication and Transcription on DNA Structure-Related ...
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Interaction of Proteins with Inverted Repeats and Cruciform ...
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The mechanism of cruciform formation in supercoiled DNA
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Interarm Interaction of DNA Cruciform Forming at a Short Inverted ...
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Dynamics of cruciform extrusion in supercoiled DNA - NIH
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Structure and dynamics of supercoil-stabilized DNA cruciforms
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DNA G-Quadruplexes as Targets for Natural Product Drug Discovery
DNA guanine (G)-quadruplexes (G4s) are unique secondary structures formed by two or more stacked G-tetrads in G-rich DNA sequences.
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G-Quadruplexes in Tumor Immune Regulation - NIH
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A Phenotypic Approach to the Discovery of Potent G-Quadruplex ...
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Dynamic Processing of Displacement Loops during ...
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Triplex H-DNA structure: the long and winding road from the ...
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DNA Triple Helices: biological consequences and therapeutic ... - NIH
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Delineation of the DNA Structural Features of Eukaryotic Core ... - NIH
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Transcription blockage by stable H-DNA analogs in vitro - PMC
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Non-canonical DNA structures are drivers of genome evolution - PMC
Non-B DNA motifs affect mutation rate and facilitate genome instability. Non-B DNA structures can pose obstacles for replicative polymerase progression during ...
[45]
The structure of proteins: Two hydrogen-bonded helical ... - PNAS
Two hydrogen-bonded helical structures for a polypeptide chain have been found in which the residues are stereochemically equivalent.
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FOLDING AMPHIPATHIC HELICES INTO MEMBRANES - NIH
High amphiphilicity is a hallmark of interfacial helices in membrane proteins and membrane-active peptides, such as toxins and antimicrobial peptides.<|control11|><|separator|>
[47]
Structure of β-sheets: Origin of the right-handed twist and of the ...
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A systematic analysis of the beta hairpin motif in the Protein Data Bank
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Helix-Turn-Helix - an overview | ScienceDirect Topics
The helix-turn-helix is defined as a simple DNA-binding motif consisting of two α helices connected by a short extended chain of amino acids, ...
[50]
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An Altered Specificity Mutation in the Lambda Repressor Induces ...
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[52]
C2H2 Zinc Finger Proteins: The Largest but Poorly Explored Family ...
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https://pubmed.ncbi.nlm.nih.gov/8144673/
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A comprehensive analysis of the Greek key motifs in protein beta ...
The Greek key motifs are the topological signature of many beta-barrels and a majority of beta-sandwich structures.
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Omega loops: nonregular secondary structures significant in protein ...
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[56]
A Novel Main Chain Motif in Proteins Bridged by Cationic Groups
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https://pubmed.ncbi.nlm.nih.gov/7601335/
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The Case of Basic Region Leucine Zipper Transcriptional Regulators
This review discusses how conformational flexibility “built” into the amino acid sequence allows bZIP proteins to interact with a large number of diverse ...
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https://doi.org/10.1016/j.jmb.2008.11.007
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Amylose - an overview | ScienceDirect Topics
Amylose typically forms a left-handed α-helical structure, in which six anhydroglucose units make up one turn of the helix. The molecular weight (Mw) of ...
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9.3: Polysaccharides - Biology LibreTexts
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The Conformation of Glycosidic Linkages According to Various ...
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Mining High-Complexity Motifs in Glycans: A New Language To ...
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Monosaccharide Diversity - Essentials of Glycobiology - NCBI - NIH
The preferred conformation of a pyranose ring is the “chair” conformation, similar to the structure of cyclohexane. The conversion from Haworth projection to ...MONOSACCHARIDES: BASIC... · MONOSACCHARIDES EXIST...
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Complex N-Glycan Number and Degree of Branching Cooperate to ...
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Dissecting structure-function of 3-O-sulfated heparin and ... - Science
Dec 22, 2021 · To date, over 400 heparin/HS-binding proteins have been identified (53), yet only a handful of 3-O-sulfated structures have been identified or ...
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C-type Lectins - Essentials of Glycobiology - NCBI - NIH
C-type lectins are CA++-dependent glycan-binding proteins that share primary and secondary structural homology in their carbohydrate-recognition domains ...
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Conformational Preferences at the Glycosidic Linkage of ...
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Structures Common to Different Glycans - Essentials of Glycobiology
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Spike N354 glycosylation augments SARS-CoV-2 fitness for human ...
Glycan shield density analysis reveals a strong correlation that viruses historically classified as 'evasion strong' [9] had significantly elevated glycan ...
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Structure of lipid bilayers - PMC - PubMed Central
The uncertainty in structural results for lipid bilayers is being reduced and best current values are provided for bilayers of five lipids.
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Sphingolipids and lipid rafts: Novel concepts and methods of analysis
In the original “lipid raft” model formalized by Simons in 1997, lipids such as cholesterol and sphingomyelin form a liquid ordered phase (Lo) in the membrane, ...
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Complementary molecular shapes and additivity of the packing ...
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Lipid Polymorphisms and Membrane Shape - PMC - NIH
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The role of cardiolipin in the structural organization of mitochondrial ...
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Cryo-EM structures of a protein pore reveal a cluster of cholesterol ...
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PI(4,5)P2: signaling the plasma membrane - PMC - PubMed Central
Nov 11, 2022 · PI(4,5)P2 is central to plasma membrane function, acting as a cofactor for signaling, transport, and structure, and is a substrate for second ...<|control11|><|separator|>
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Zinc finger proteins: insights into the transcriptional and post ...
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Structures and biological functions of zinc finger proteins and their ...
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Quantifying Modularity in the Evolution of Biomolecular Systems - PMC
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Mechanism of misfolding of the human prion protein revealed by a ...
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The G-quadruplex ligand CX-5461: an innovative candidate for ...
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Development of Glycan-masked SARS-CoV-2 RBD vaccines ... - NIH
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De novo design of protein structure and function with RFdiffusion
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Importance of the PAM sequences in CRISPR-Cas9 gene editing
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Protein structure prediction via deep learning: an in-depth review
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Hierarchical design of artificial proteins and complexes toward ...
A central goal of “synthetic structural biology” is the design and construction of artificial proteins and protein complexes as desired. In this paper, I review ...