Nucleic acid quaternary structure refers to the interactions between separate nucleic acid molecules, or between nucleic acid molecules and proteins. The concept is analogous to protein quaternary structure, but as the analogy is not perfect, the term is used to refer to a number of different concepts in nucleic acids and is less commonly encountered.^[1] Similarly other biomolecules such as proteins, nucleic acids have four levels of structural arrangement: primary, secondary, tertiary, and quaternary structure. Primary structure is the linear sequence of nucleotides, secondary structure involves small local folding motifs, and tertiary structure is the 3D folded shape of nucleic acid molecule. In general, quaternary structure refers to 3D interactions between multiple subunits. In the case of nucleic acids, quaternary structure refers to interactions between multiple nucleic acid molecules or between nucleic acids and proteins. Nucleic acid quaternary structure is important for understanding DNA, RNA, and gene expression because quaternary structure can impact function. For example, when DNA is packed into heterochromatin, therefore exhibiting a type of quaternary structure, gene transcription will be inhibited.

DNA quaternary structure is used to refer to the binding of DNA to histones to form nucleosomes, and then their organisation into higher-order chromatin fibres.^[2] The quaternary structure of DNA strongly affects how accessible the DNA sequence is to the transcription machinery for expression of genes. DNA quaternary structure varies over time, as regions of DNA are condensed or exposed for transcription. The term has also been used to describe the hierarchical assembly of artificial nucleic acid building blocks used in DNA nanotechnology.^[3]

The quaternary structure of DNA refers to the formation of chromatin. Because the human genome is so large, DNA must be condensed into chromatin, which consists of repeating units known as nucleosomes. Nucleosomes contain DNA and proteins called histones. The nucleosome core usually contains around 146 DNA base pairs wrapped around a histone octamer.^[4]  The histone octamer is made of eight total histone proteins, two of each of the following proteins: H2A, H2B, H3, and H4.^[5]  Histones are primarily responsible for shaping the nucleosomes, therefore drastically contributing to chromatin structure.^[4]  Histone proteins are positively-charged and therefore can interact with the negatively-charged phosphate backbone of DNA.^[5]  One portion of core histone proteins, known as histone tail domains, are extremely important for keeping the nucleosome tightly wrapped and giving the nucleosome secondary and tertiary structure. This is because the histone tail domains are involved in interactions between nucleosomes. The linker histone, or H1 protein, is also involved maintaining nucleosome structure. The H1 protein has the special role of ensuring that DNA stays tightly wound.^[4]

Modifications to histone proteins and their DNA are classified as quaternary structure. Condensed chromatin, heterochromatin, prevents transcription of genes. In other words, transcription factors cannot access wound DNA-^[6]  This is in contrast to euchromatin, which is decondensed, and therefore, readily accessible to the transcriptional machinery. DNA methylation to nucleotides influences chromatin quaternary structure. Highly methylated DNA nucleotides are more likely found within heterochromatin whereas unmethylated DNA nucleotides are common in euchromatin. Furthermore, post-translational modifications can be made to the core histone tail domains, which lead to changes in DNA quaternary structure and therefore gene expression. Enzymes, known as epigenetic writers and epigenetic erasers, catalyze either the addition or removal of several modifications to the histone tail domains. For instance, an enzyme writer can methylate Lysine-9 of the H3 core protein, which is found in the H3 histone tail domain. This can lead to gene repression as the chromatin gets remodeled and resembles heterochromatin. However, dozens of modifications can be made to histone tail domains. Therefore, it is the sum of all those modifications that determine whether chromatin will resemble heterochromatin or euchromatin.^[7]

RNA is subdivided into many categories, including messenger RNA (mRNA), ribosomal RNA (rRNA), transfer RNA (tRNA), long non-coding RNA (lncRNA), and several other small functional RNAs. Whereas many proteins have quaternary structure, the majority of RNA molecules have only primary through tertiary structure and function as individual molecules rather than as multi-subunit structures.^[1] Some types of RNA show clear quaternary structure that is essential for function, whereas other types of RNA function as single molecules and do not associate with other molecules to form quaternary structures. Symmetrical complexes of RNA molecules are extremely uncommon compared to protein oligomers.^[1] One example of an RNA homodimer is the VS ribozyme from Neurospora, with its two active sites consisting of nucleotides from both monomers.^[9] The best known example of RNA forming quaternary structures with proteins is the ribosome, which consists of multiple rRNAs, supported by rProteins.^[10][11] Similar RNA-Protein complexes are also found in the spliceosome.