Ref J3
Computational Service
Confidence Reported
Scoped After Feasibility Review
Service Overview
Stapling locks a peptide into the helical conformation it must adopt to bind, paying the entropic cost once during synthesis rather than repeatedly during binding. Done well, it improves affinity, protease resistance and sometimes cell entry. Done carelessly, it abolishes binding by fixing the wrong geometry. We identify which positions can carry a staple without disturbing the binding face, design the crosslink chemistry and geometry, and model the constrained peptide in complex with the target.
Key Features & Advantages
Staple Positions Screened Systematically
All i,i+3, i,i+4 and i,i+7 options are evaluated for geometric feasibility and for whether they sit on the non-binding face, rather than choosing by convention.
Helicity Predicted And Verified
Helical propensity is assessed before and after constraint, and simulation is used to confirm that the staple actually stabilises the intended conformation.
Binding Face Protected
Designs explicitly avoid placing crosslinks on residues that contact the target, which is the most common reason stapled peptides lose activity.
Alternative Constraints Compared
Hydrocarbon stapling, lactam bridges, disulfides and other crosslinks are compared for feasibility and stability in your specific sequence context.
Where This Service Is Used
1Stabilising a helical peptide that binds a protein–protein interface
2Improving protease resistance and half-life of a helical lead
3Attempting intracellular delivery of a peptide inhibitor
4Rescuing a peptide with good affinity but poor conformational stability
5Designing constrained analogues of a natural helical ligand
Methods and Techniques Applied
1Structural analysis of the peptide–target complex and identification of the binding face
2Helical propensity analysis across the sequence, with and without constraint
3Systematic staple position scanning across spacing options with geometric feasibility checking
4Crosslink chemistry selection and modelling of the constrained backbone
5Molecular dynamics of the stapled peptide alone and in complex to verify conformational stabilisation
6Property assessment covering solubility, aggregation, hydrophobicity and permeability risk
What We Need From You
1Peptide sequence and, where available, the structure of the complex with the target
2Known SAR identifying which residues are essential for binding
3The objective: affinity, stability, cell penetration or a combination
4Synthesis capability, since stapling chemistry imposes real constraints
What You Receive
1Designed stapled peptides with staple position, chemistry and stereochemistry specified
2Complex models with the constrained peptide bound to the target
3Helicity and stability analysis comparing constrained and unconstrained forms
4Property predictions including the hydrophobicity increase that stapling usually brings
5Prioritised synthesis and testing plan across the design set
What We Compute and Report
1Helical propensity across the sequence, before and after constraint
2Geometric feasibility for every staple position and spacing considered
3Complex models confirming the constraint does not occlude the binding face
4Simulation-based verification that the staple stabilises the intended conformation
5Hydrophobicity and aggregation risk change introduced by the crosslink
Questions We Are Asked Before Scoping
Will stapling improve cell permeability?
▸Sometimes, and it is sequence-dependent rather than a general property of stapled peptides. Charge, hydrophobicity and staple position all matter, and the literature contains as many failures as successes.
Can any peptide be stapled?
▸Only helical or helix-capable segments benefit. For non-helical peptides, cyclisation or other constraint strategies are more appropriate, and we will say so at scoping.
How many variants should we make?
▸Typically ten to twenty spanning positions and chemistries. Stapling outcomes are difficult to predict precisely, so a designed panel is more efficient than betting on one construct.
Interpretation and Limitations
Computational predictions prioritise hypotheses; they do not independently establish binding, biological activity, therapeutic efficacy, safety or clinical validity. Performance depends on input quality, target class, the structural evidence available and the applicability domain of the selected methods. Scores used for ranking are comparative devices and should not be read as measured quantities. All deliverables are for research use only and are not intended for diagnostic or therapeutic use.
Is This the Right Service for You?
Choose this when
The bioactive conformation is helical and the free peptide is disordered
Affinity could be improved by paying the entropic cost during synthesis
Previous stapling attempts abolished activity and the cause is unknown
Consider another service when
The peptide is not helical
Cyclic Peptide Design A smaller, more drug-like molecule is acceptable
De Novo Small Molecule Design What Goes Wrong, and How We Handle It
These are the failure modes that produce confident-looking results which do not survive the next experiment. Each one is designed against rather than discovered afterwards.
A staple placed across the binding face
The binding face is identified from the complex first, and crosslink positions are restricted to the opposite surface.
The constraint locking a conformation that is not the bound one
Simulation verifies that the staple stabilises the intended conformation rather than an alternative helical register.
Hydrophobicity increases causing aggregation or non-specific binding
The property change introduced by each crosslink chemistry is predicted and reported alongside the affinity rationale.
A Worked Example
Why the first stapled series lost all activity
The situation
Three stapled analogues of an active helical peptide showed no measurable binding.
What the work involved
The complex was modelled, contact residues were mapped, and the existing staple positions were checked against them; alternative i,i+4 and i,i+7 placements were then scanned on the non-binding face.
What came back
All three original staples sat on contact residues. Fourteen redesigned analogues were delivered on the opposite face, with predicted helicity gain and the hydrophobicity change quantified for each.
Illustrative of the shape this work takes. Details are generalised, no client or target is identified, and scope and outcome vary with the system in question.
Service Workflow
1
Scientific Consultation
We discuss the objective, the decision it supports and the data you hold. Nothing is quoted before we understand what the result has to answer.
2
Feasibility Review
We check that the data, target class and available structural evidence can support the proposed approach, and say plainly where they cannot.
3
Technical Proposal
Scope, methods, deliverables, timeline and price are confirmed in writing, together with the limitations we expect to report.
4
Computation and QC
The analysis runs on pinned tool versions in a containerised environment, with quality checkpoints and method comparison where that is informative.
5
Report and Follow-Up
You receive the ranked results, the documented methods, the limitations and a proposed validation plan, plus support in interpreting them.
Service Process
1
Online Consultation
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2
Solution Matching
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3
Service Contract
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4
Project Execution
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5
Data Delivery
Specifications & Turnaround
Note: ICDMO delivers computational (in silico) services. Results prioritise hypotheses for testing; they do not by themselves establish binding, biological activity, efficacy or safety. All deliverables are for research use only and are not intended for diagnostic or therapeutic use. Downstream experimental work is scoped separately and executed through qualified partners.
Get a Custom Quote
Our scientific team responds within 24 hours with a detailed technical proposal and pricing tailored to your project.
Contact Us Online ConsultationStandard Deliverables
✓Sequence-verified final product
✓Full QC documentation
✓Certificate of Analysis (CoA)
✓Electronic data files
✓Project completion report
Why ICDMO?
Computational CDMO Focus
Reproducible, Versioned Pipelines
Confidence & Limitations Reported
Experiment-Aware Recommendations
Response Within One Business Day