Membrane Protein Design

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Overview

Membrane proteins carry a large share of drug targets and a disproportionate share of the technical difficulty. Design and engineering must account for the lipid environment, the packing of transmembrane helices, the conformational cycling that transporters and channels depend on, and the practical problem of expressing and purifying the result. We model these systems in realistic bilayers and design for stability, conformational state or function while keeping the folding and expression constraints in view.

Schematic: substitutions are scored at every position for stability and function, with catalytic and binding residues protected from redesign.

Key Advantages

Realistic Bilayer Environment

Systems are modelled in lipid compositions matched to the relevant membrane, since transmembrane behaviour depends on the bilayer and not only on the protein.

Helix Packing Designed Explicitly

Transmembrane helix interfaces and packing motifs are analysed and designed, as they govern both fold stability and oligomeric assembly.

Lipid-Facing Surfaces Treated Separately

Residues facing lipid follow different design rules from those facing water or the protein core, and designs respect that distinction rather than applying uniform criteria.

Conformational States Modelled

For transporters, channels and receptors, multiple functional states are modelled so that designs can stabilise the state the project requires.

Where This Service Is Used

Thermostabilising a GPCR or transporter for structural studies or assay development

Designing constructs that trap a specific conformational state

Engineering improved expression and detergent or nanodisc stability

Modelling and designing ion channel gating behaviour

Designing de novo transmembrane assemblies such as pores or scaffolds

Methods and Techniques Applied

Membrane topology determination and structure prediction or modelling in a bilayer context

Bilayer system construction with appropriate lipid composition and equilibration

Molecular dynamics to characterise helix packing, lipid interactions and conformational behaviour

Stability-directed mutational scanning with membrane-aware scoring functions

State-selective design targeting active, inactive or intermediate conformations

Expression and construct design: truncations, fusion partners, thermostabilising mutation sets

What We Need From You

Sequence and, where available, structure or related family structures

The functional state of interest and any ligands, lipids or ions involved

Expression and purification history, including where the current construct fails

The objective: stability, state trapping, expression, or de novo design

What You Receive

Designed sequences or construct definitions with the rationale for each change

Membrane-embedded structural models with lipid interaction analysis

Simulation results characterising stability and conformational behaviour

Ranked mutation sets for thermostabilisation or state selection

Construct design recommendations for expression and purification trials

What We Compute and Report

Membrane-embedded models with lipid contact and helix packing analysis

Predicted stability change per substitution using membrane-aware scoring

Conformational state populations observed across simulation replicates

Construct-level assessment: boundaries, fusion partners and predicted expression risk

Simulation metrics for bilayer insertion depth, tilt and interaction persistence

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.

Specifications

Item	Specification	Notes
System types	GPCRs, channels, transporters	Including de novo transmembrane designs
Simulation	Multi-µs in explicit bilayer	Lipid composition chosen per system
Typical turnaround	5–10 weeks	Membrane simulation dominates the timeline
Variants delivered	15–60 designs	Including construct-level variants

Service Workflow

Step 01

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.

Step 02

Feasibility Review

We check that the data, target class and available structural evidence can support the proposed approach, and say plainly where they cannot.

Step 03

Technical Proposal

Scope, methods, deliverables, timeline and price are confirmed in writing, together with the limitations we expect to report.

Step 04

Computation and QC

The analysis runs on pinned tool versions in a containerised environment, with quality checkpoints and method comparison where that is informative.

Step 05

Report and Follow-Up

You receive the ranked results, the documented methods, the limitations and a proposed validation plan, plus support in interpreting them.

Is This the Right Service for You?

Choose this service when

A receptor, transporter or channel must be stabilised for structural or assay work

A specific conformational state needs trapping

Expression or detergent stability is blocking the programme

Consider another service when

The protein is soluble

Protein Stability & Thermostability Engineering

The question is ligand binding at a known site

Molecular Docking

What Goes Wrong, and How We Handle It

The failure modes that produce confident-looking results which do not survive the next experiment. Each one is designed against rather than discovered afterwards.

Systems are built in lipid compositions matched to the relevant membrane, because transmembrane behaviour depends on the bilayer.

Case Studies

The situation

The receptor was too unstable in detergent to progress to structure determination.

What the work involved

The receptor was modelled and simulated in a matched bilayer, helix packing and lipid interactions were analysed, and stability scanning was run with membrane-aware scoring while conformational state was tracked.

What came back

Twenty-four candidate mutations ranked by predicted stabilisation, annotated with which conformational state each was expected to favour, plus construct boundary and fusion recommendations.

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.

Questions We Are Asked Before Scoping

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 in Touch
about Membrane Protein Design

Tell us about the target, the data you hold and the decision the result needs to support. A scientist reviews every enquiry and replies within one business day.

Feasibility reviewed before any scope or price is fixed

Methods, parameters, confidence and limitations in every report

Confidentiality agreement available before data is shared