Authors
Ying Chou, Igor Novikov, Daniel Pierson, Kenneth A Marx, Arani Chanda, Valeri Barsegov
Published in
Molecular therapy. Nucleic acids. Volume 37. Issue 3. Pages 103056. Sep 08, 2026. Epub Aug 12, 2026.
Abstract
Phosphorodiamidate morpholino oligonucleotides (PMOs) are a class of antisense oligonucleotides. While PMOs have enabled several nucleic acid therapeutics, their structural and energetic solution properties remain poorly understood. Using solution viscosity measurements combined with computational molecular modeling, we explored interactions of therapeutic 22-mer, 25-mer, and 30-mer PMOs in concentrated solutions. Self-association of PMO monomers involves non-specific interactions, is energetically favorable (with estimates of -32 to -67 kcal/mol interaction energies), and exhibits biphasic kinetics involving a fast phase of hydrophobic anchoring followed by a slower phase associated with optimization of intermolecular base pairing and stacking interactions. The final complexes possess broad self-association interfaces of ∼700-1,600 Å2. Accurate interpretation of the viscosity vs. concentration data for concentrated PMO solutions must account for PMO dimer formation, as supported by the molecular dynamics simulations. Formation of higher-order PMO species was inferred from viscosity-concentration profiles based on models 1-4: for the 25-mer at concentrations above 160 mg/mL (dimerization) and 240 mg/mL (trimerization), and for the 30-mer above 190 mg/mL (dimerization) and 270 mg/mL (trimerization), respectively. The results provide atomic-level details on PMO structure, molecular properties, and interaction energies in concentrated environments, identifying weak preferential functional group interaction patterns that underlie thermodynamic stability.
PMID:
42668701
Bibliographic data and abstract were imported from PubMed on 30 Aug 2026.
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