Ref J2
Computational Service
Confidence Reported
Scoped After Feasibility Review
Service Overview
Head-to-tail cyclisation removes the charged termini that proteases and clearance mechanisms exploit, and it restricts the conformational ensemble so that less binding entropy is lost. Both effects are worth having, and both depend on getting the ring size and the sequence right. We design cyclic peptides against a target site, sample the accessible ring conformations properly, model the complex, and assess the permeability that cyclic peptides may — but frequently do not — achieve.
Key Features & Advantages
Ring Conformations Sampled, Not Assumed
Cyclic peptides occupy a restricted but still substantial conformational space; we generate ensembles and assess the population of the bioactive conformation rather than modelling a single ring.
Cyclisation Chemistry Chosen Deliberately
Head-to-tail, side-chain-to-tail, disulfide and thioether strategies are compared for the sequence in question, since the chemistry affects both stability and achievable geometry.
Permeability Predicted For The Right Chemical Space
Assessment uses models developed for beyond-rule-of-five macrocyclic space, including intramolecular hydrogen bonding and conformational shielding.
Stability Gains Quantified
Predicted protease resistance is compared with the linear parent so the benefit of cyclisation is stated rather than assumed.
Where This Service Is Used
1Improving protease stability and half-life of a linear peptide lead
2Constraining a bioactive conformation to improve binding affinity
3Designing cyclic peptides against extended protein–protein interfaces
4Exploring oral or cell-permeable peptide therapeutics
5Designing libraries for mRNA or phage display with cyclisation built in
Methods and Techniques Applied
1Analysis of the linear parent or the target site to define the cyclisation strategy
2Ring size and closure position scanning with strain and geometry assessment
3Conformational ensemble generation with enhanced sampling for the cyclic backbone
4Complex modelling with the target and assessment of bioactive conformation population
5Molecular dynamics of the complex to test stability and the persistence of key contacts
6Permeability and property prediction using macrocycle-appropriate models
What We Need From You
1Target structure and site, or the linear peptide sequence to be cyclised
2Any known bioactive conformation or SAR data from the linear series
3Required properties: stability, permeability, route of administration
4Available cyclisation chemistry and synthesis constraints
What You Receive
1Designed cyclic sequences with the cyclisation chemistry and ring size specified
2Conformational ensembles with bioactive conformation population estimates
3Complex models with interaction analysis
4Predicted stability, solubility and permeability profiles
5Synthesis notes and a prioritised testing plan
What We Compute and Report
1Ring conformational ensembles with the population of the bioactive conformation
2Ring strain and closure energetics per cyclisation position considered
3Complex models with interaction analysis for the bound conformation
4Permeability estimates computed with macrocycle-appropriate models
5Predicted protease resistance compared against the linear parent
Questions We Are Asked Before Scoping
Will cyclisation make our peptide orally available?
▸Sometimes, but it is not automatic. Oral macrocycles typically need low hydrogen-bond donor counts, N-methylation and conformational shielding. We predict permeability and state the risk rather than assume the benefit.
How do we choose ring size?
▸By scanning closure positions and ring sizes computationally and assessing strain, geometry and how well the bioactive conformation is preserved. The scan is part of the service.
Is conformational prediction reliable for macrocycles?
▸It is harder than for rigid small molecules. We use enhanced sampling and deliver ensembles with populations rather than a single conformation presented as definitive.
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
A linear peptide lead is cleared or degraded too quickly
Constraining the conformation could recover binding entropy
Oral or cell-permeable peptide chemistry is the objective
Consider another service when
The bioactive conformation is a defined helix
Stapled & Constrained Peptide Design Non-peptidic chemistry would suit the target better
Macrocycle 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 single modelled ring conformation standing in for the real ensemble
Enhanced sampling generates ensembles, and the population of the bioactive conformation is quantified rather than assumed.
Cyclisation assumed to deliver oral exposure
Permeability is predicted with macrocycle-appropriate models and reported as a risk, since most cyclic peptides are not orally available.
Ring size chosen by convention
Closure position and ring size are scanned computationally, with strain and geometry assessed for each option.
A Worked Example
Choosing where to close the ring
The situation
A linear 11-mer bound well but had a plasma half-life of minutes, and the team had no basis for choosing a cyclisation point.
What the work involved
Every closure position was enumerated, ring strain and geometry were assessed, ensembles were generated for the viable options, and the population of the bound conformation was computed for each.
What came back
Two closure positions retained the bioactive conformation as a dominant state; three others distorted the binding face. Six designs were delivered with predicted stability gain and permeability risk 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