Macromolecules such as proteins, peptides, oligonucleotides, antisense molecules, bi-conjugates and hetero-conjugates are emerging as a novel and important class of entities for drug discovery and vaccine development, serving as both targets and therapeutic agents. With the rise of custom and chemically modified molecules, the need for integrated sequence-level and atom-level representations has been a significant informatics challenge.
To address this, the CDD Research Informatics team has developed a tool that allows scientists to generate atomistic structures from sequences, register them, compute a wide range of chemical properties, and associate biological assay data. By integrating cheminformatics (atoms and bonds) with bioinformatics (monomer sequences and data mapping), the platform enables in-depth analysis of molecular interactions and modifications- bridging theory and application to accelerate therapeutic innovation.
Designing Macromolecules:
To design any macromolecule (peptides, oligonucleotides, siRNA, antisense oligonucleotides (ASOs) or conjugates):
- Open the Structure Editing Tool
- Switch the mode to Macromolecule
You can begin by uploading a file or pasting sequence data from your clipboard.
Supported formats include:
- MDL Molfile V3000
- Sequence
- FASTA
- IDT format
- HELM notation
- Ketcher (Ket) file
If you're entering a sequence, specify the type of input sequence (e.g., DNA, RNA, peptide) to ensure accurate interpretation and processing.
For peptides, both one-letter and three-letter code formats are supported.
Alternatively, enter the sequence directly on the drawing canvas by switching to Sequence Mode, as shown below-
Sequence Mode and Mixed Sequences:
Three toggles - RNA, DNA, and PEP - are available to specify different sequence types.
You can mix these sequence types directly on the canvas. The system will automatically handle the bond connections between different sequence types, enabling the creation of hybrid entities such as
- RNA–DNA constructs
- Peptide–RNA conjugates
- Peptide–DNA conjugates
- siRNA–Peptide conjugates
- Glycopeptides or GlycoRNA
- Lipid–RNA conjugates
- Peptide Nucleic Acid (PNA) hybrids
- Protein–Oligonucleotide hybrids
Use Snake View mode to visualize branch points and connections (e.g., lysine-ribose linkages) as illustrated in the image below.
Chemically Aware Macromolecules:
Canvas ensure that the chemical integrity of all designed macromolecules is fully preserved. Whether you are designing a simple peptide or unique, a highly modified oligonucleotide, or any complex hybrid structure, the system supports accurate chemical representation and validation at every step. This empowers you to draw and customize macromolecules freely, exactly as you envision them- no matter how novel or chemically intricate.
With advanced chemical awareness, the tool automatically manages:
- Correct bond formations and stereochemistry
- Unusual modifications and non-standard residues
- Hybrid entities combining peptides, nucleic acids, and other biomolecules
- Compatibility with diverse file formats for seamless integration and analysis
Modifications:
Any chemical modification can be added directly on the canvas- either by clicking a modified monomers and chemicals from the library in the right-side panel or by drawing custom chemical structures from Molecule Mode.
Available building blocks in the canvas include-
- Color-coded natural and unnatural amino acids
- Ambiguous amino acids
- Common modifications (e.g., N-methyl, acetyl, C-terminal amide)
- RNA builder for custom nucleotide creation
- Modified bases, sugars, and phosphates
- PNA, Super-G, and other synthetic nucleotides
- Dyes (e.g., Cy5, TAMRA), chelators (e.g., DOTA), polymers (e.g., PEG)
Modified Peptides and branching
Use Sequence Mode to add modified amino acids. For branched peptides:
- Switch to Snake Mode.
- Drag modified or unmodified amino acids onto the canvas.
- Create bonds at desired points- an input dialog will prompt you to specify the connection type.
Sequence mode:
This syntax allows intuitive visual and functional representation of DNA, RNA, and peptides in sequence mode, with symbols and annotations to denote modifications and structural elements. When hovering over each monomer, the chemical structure is highlighted to provide visual clarity and support interaction with complex biomolecule components.
| Symbol | Meaning |
| @ | Indicates a chemical modification or custom chemistry between monomers (e.g., non-standard linkers or branched attachments). |
| _ (underscore) | Denotes a modified peptide monomer (e.g., phosphorylated or methylated amino acid). |
| 🔲 (Caged Letter) |
Represents a deoxyribose sugar in a nucleotide (commonly used for DNA bases). For example, a boxed A signify deoxyadenosine.
|
|
° (Degree Sign)
|
Indicates a non-phosphorylated building block - often used at the ends of nucleotide chains (e.g., 5' or 3' terminal modifications). |
| Grey shaded letter | Represents a modified base in the nucleotide building block. |
| Solid grey degree sign | Indicates a modified sugar in the nucleotide. |
Disulfide Bridge:
A disulfide bridge (or disulfide bond) can be formed between the sulfur atoms of the thiol (-SH) groups of two cysteine residues within any sequence, helping to stabilize the peptide’s structure.
Modified RNA:
Using the RNA Builder in the right-side panel, you can add your choice of base, sugar, or phosphate group, or select from the prebuilt nucleotides available in the library.
Custom presets can also be created and temporarily stored on the canvas, allowing you to reuse your own modified nucleotide designs at any point at Vault (at the moment this is not shared by other users).
Antisense / Double-Stranded DNA or RNA:
To generate an antisense strand, simply select nucleotides within the chain and either right-click to choose “Create RNA Antisense Strand” or “Create DNA Antisense Strand,” or use the antisense icon located in the top toolbar.
You can also build an antisense strand more creatively in Snake Mode, where you have greater flexibility to manually design a complementary strand for a specific region.
Additionally, by right-clicking within the RNA Builder, you can modify selected nucleotides—allowing you to change the base, sugar, or phosphate for all highlighted nucleotides at once.
Chemical Properties:
Key chemical properties such as molecular formula, molecular weight, isoelectric point (pI), and extinction coefficient can be instantly viewed at the canvas before registering these entities at Vault. Simply click the "Chemical Properties" icon located in the top toolbar.
These properties are dynamically calculated based on the selected structure and are available for a wide range of macromolecules, including both oligonucleotides and peptides. The display updates automatically as you modify the molecule- allowing for real-time feedback on how chemical changes affect the overall composition.
See the attached images below for examples of how these properties appear for oligos and peptides.
After designing your macromolecule, please refer to this article to complete the registration of these entities.