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Eric Westhof is a structural biochemist whose research concerns the architecture and molecular interactions of RNA. His institutionally hosted CV identifies work at Strasbourg's IBMC and a professorship in structural biochemistry.^[ref]

With N. B. Leontis, Westhof developed a geometric nomenclature for RNA base-pair geometry. The classification records the interacting RNA base-pair edges and the relative orientations of the two glycosidic bonds, allowing noncanonical base pairs to be described systematically.^[ref]

An important distinction is between two kinds of orientation. The glycosidic torsion angle $\chi$ describes how one base rotates relative to its own sugar, giving syn glycosidic conformation or anti glycosidic conformation. The pair's cis/trans descriptor instead relates the two glycosidic bonds across the base-pair interaction. Reporting one descriptor does not automatically report the other.

A geometric family also leaves room for different base identities. The question of RNA base-pair isostericity is whether substitutions can preserve the relevant relative placement and shape sufficiently to support a similar structural role. This makes geometry useful when comparing homologous RNA structures even when their sequences differ.^[ref]

Westhof's contribution helped connect structural observations with a reusable language for comparing RNA folds, rather than restricting descriptions to the familiar sequence letters or canonical base pairs.

The Hoogsteen base-pair edge is a contact surface of a nucleobase distinct from its Watson-Crick base-pair edge and sugar base-pair edge. For a purine, it is the side containing N7 and the exocyclic group at position 6; for example, adenine presents N7 and its N6 amino group on this side. The structural classification extends the corresponding category to the CH edge of pyrimidines.^[ref]

The word describes one partner's contacting edge, not a complete pair or a mandatory rotation of the base. A complete RNA base-pair geometry identifies the second partner's edge and the cis/trans orientation of the glycosidic bonds. The primary matrices include Hoogsteen–Watson–Crick, Hoogsteen–Hoogsteen and Hoogsteen–sugar contacts.^[ref]

An original counting example makes this useful. Fix one adenine as the labeled first partner and stipulate that it uses its Hoogsteen edge. The second partner still has three edge categories available; each can appear with a cis or trans relationship. There are therefore $3\times 2=6$ labeled edge/orientation descriptions before specifying the second base's identity. This counts descriptions, not six experimentally established partners for that particular adenine.

Edge identity must also be distinguished from chemical role. N7 of ordinary neutral adenine is a hydrogen bond acceptor, while its amino group can supply a hydrogen bond donor. A favorable contact requires an appropriately positioned complementary group, not merely two bases facing sides with the same category name. Structural conditions and chemical state matter.

When annotating an experimental RNA structure, record the interacting atoms and the two glycosidic bonds, rather than classifying from the sequence alone. An A–U pair can use a different geometry from the canonical Watson–Crick arrangement. Conversely, an edge category can recur with different base identities. This is why RNA base-pair isostericity is evaluated within explicit geometric families rather than inferred only from the letters A, C, G and U.

Neocles B. Leontis studied RNA structure and molecular recognition at Bowling Green State University. His institutional profile identifies him as a chemistry professor and biology adjunct working on nucleic acids.^[ref]

With E. Westhof, Leontis proposed a systematic classification of RNA base-pair geometry using three possible interacting RNA base-pair edges and two relative glycosidic-bond orientations.^[ref]

A small counting argument explains the12basic families. Write $W,H,S$ for the Watson–Crick, Hoogsteen and Sugar edges. Treating interchange of the two bases as the same edge-family givesThere are6unordered choices with repetition. Each can have cis or trans relative glycosidic-bond orientation, giving $6\times 2=12$. This counts geometric families, not nucleotide sequences or the number of hydrogen bonds in every individual interaction.

The classification provides a way to annotate noncanonical base pairs and compare structural motifs. The2001 paper also explains how geometric families can reveal RNA base-pair isostericity, connecting observed structures to plausible substitutions in related sequences.^[ref]

The RNA IsoDiscrepancy Index, abbreviated IDI, is a numerical measure of how two base pairs differ in the geometry relevant to their attached backbones. Lower values indicate closer RNA base-pair isostericity. Jesse Stombaugh, Craig L. Zirbel, Eric Westhof and Neocles B. Leontis introduced it to make comparisons more quantitative than assigning pairs only to broad geometric families.^[ref]

The comparison considers the separation of the ribose $\mathrm{C}{1}^{\prime }$ atoms and the relative positions and orientations of the bases at their glycosidic bonds. The attachment nitrogen is N1 for a pyrimidine and N9 for a purine. Thus matching the distance between two sugar attachment points alone does not establish matching base orientation. The published construction handles in-plane alignment and comparisons requiring an out-of-plane flip separately.^[ref]

IDI has units of ångströms, not a dimensionless probability scale. In the in-plane case, the method weights an orientation angle $\theta$ by a 2-ångström length scale. An original illustration of that rotation term isThis is one weighted rotation contribution, not the complete IDI formula. Translation, separation and the paired orientation comparisons also matter. Expressing an angle in radians is essential to this length interpretation.^[ref]

The authors calibrated their classification using structural distributions: IDI at most 2.0 ångströms is isosteric, above 2.0 through 3.3 ångströms is near-isosteric, and larger values are more dissimilar. These are the study's method-specific cutoffs. A chosen score of 1.8 therefore falls in its first category, whereas 2.6 falls in its second; neither is an energy or a probability.^[ref]

Interchanging the two structures being compared leaves the discrepancy unchanged; reversing the nucleotide order within only one base pair is a different operation. An RNA isostericity matrix can display such comparisons, but sequence context and model quality still affect interpretation. A geometrically plausible substitution is a structural hypothesis, not a guarantee of unchanged folding stability or molecular recognition.

The Watson-Crick base-pair edge is the nucleobase contact surface used in ordinary canonical base pairing. In RNA, the familiar adenine–uracil and guanine–cytosine contacts use this edge on both partners with cis-oriented glycosidic bonds in the geometric classification.^[ref]

For adenine, this edge includes its N1 ring nitrogen and N6 amino group. These provide a hydrogen bond acceptor and a hydrogen bond donor, respectively, in the ordinary neutral chemical form. The N6 group also borders the Hoogsteen base-pair edge; the classification divides contact regions, not disjoint lists in which every atom must belong to only one edge.^[ref]

A simple canonical A–U example has the uracil N3 hydrogen directed toward adenine N1 and an adenine N6 hydrogen directed toward uracil O4. These are the two conventional hydrogen bonds. In the corresponding G–C geometry, three conventional hydrogen bonds can form. The number of bonds is a property of the chemical pairing arrangement, not the definition of the edge.

The term also does not require the second base to use its own Watson–Crick edge. A Watson–Crick–Hoogsteen contact uses the named edge on one partner and the Hoogsteen base-pair edge on the other. Even a Watson–Crick–Watson–Crick edge combination can have a trans relationship of glycosidic bonds, placing it in a different family from the ordinary cis contact.^[ref]

An original comparison separates the information being recorded. “A contacts U” supplies two identities. “Both use Watson–Crick edges” adds two contact surfaces. “The glycosidic bonds are cis” adds their relative orientation. Only the full description identifies the canonical family; sequence identity alone cannot determine the geometry. Experimental structural coordinates or restraints are needed to decide which arrangement occurs in a particular molecule.

The edge framework consequently covers both canonical and noncanonical base pairs without equating every use of a familiar contact surface with the familiar double-helix geometry. It also makes RNA base-pair isostericity a geometric question rather than a simple count of hydrogen bonds.