Membrane protein interaction analysis using Biacore™ SPR technology: Published examples and key considerations

This whitepaper is part of Biacore™ SPR applications series.

In this series, we explore how Biacore™ SPR technology supports a wide range of applications—from membrane protein analysis to fragment screening, ADCs, and beyond. Each article draws on published studies and practical case data to help scientists get the most out of SPR and label‑free interaction analysis.

Key takeaways:

• Membrane proteins are essential drug targets but are technically challenging to work with due to instability outside lipid environments.
• Published studies demonstrate successful use of detergents, nanodiscs, amphipols, and SMALPs to stabilize membrane proteins for SPR analysis.
• Biacore SPR technology supports both high‑throughput interaction screening and in‑depth kinetic characterization, allowing researchers to choose the level of detail required for each experiment.
• SPR can reveal how solubilization method, protein state (native vs. denatured), and buffer conditions influence binding activity, enabling more informed experimental design.

Introduction to membrane proteins

Membrane proteins are the molecular targets for approximately 60% of current validated medicines—making them a major molecular target for drug discovery (1). They have numerous key roles within the body including:

Transport: Moving specific ions or molecules across the membrane (2).

Cell signaling: Extracellular signals are received and transduced by proteins, which then trigger intracellular signaling cascades (3). G-protein-coupled receptors (GPCRs) are crucial cellular signaling hubs within cell membranes.

Since membrane proteins have key applications within the body, when mutations occur it often results in disease (4).

Challenges in membrane protein analysis

Multiple analytical hurdles exist in membrane protein binding assays. The primary analytical obstacle is membrane protein instability outside of the membrane. Membrane proteins are hydrophobic and sit within lipid bilayers. This makes them difficult to solubilize and purify without denaturing or causing loss of activity (5). Membrane proteins often lose their native conformation when removed from the lipid bilayer, which leads to instability and an increased tendency to aggregate (6). Low membrane protein abundance creates another key analytical issue. Membrane proteins have a low abundance within cells, so it's difficult to obtain a quantity sufficient for protein analysis (7). They are unstable and difficult to purify, further decreasing the amount of protein available (8). As a result of these challenges, it is difficult to obtain structural and functional analysis of membrane proteins, which complicates efforts to investigate disease-related variants or novel drug targets. Specialized analysis tools are required to provide insight into membrane proteins and guide membrane protein analysis for drug screening and discovery; Biacore SPR analysis requires relatively small quantities of protein compared to other analytical methods making it well-suited to membrane protein analysis.

Extracting membrane proteins for characterization

To analyze membrane proteins, they need to be extracted from membranes while retaining their structure and function. Three major approaches are used to extract membrane proteins for characterization.

Detergent or lipid solubilization

Extraction of membrane proteins from the lipid bilayer is often accomplished using detergents to destabilize the membrane and solubilize the membrane protein. Different detergents can be selected depending on the properties of the membrane protein (9). The detergents form a micellar structure around the hydrophobic areas of the membrane protein and prevent it from denaturing or aggregating, enabling solubilization (8).

Nanodiscs

Nanodiscs are formed of a discoidal lipid bilayer surrounded by two membrane scaffold protein belts (10, 11). The membrane proteins are solubilized using detergents and reconstituted into nanodiscs, where the lipid bilayer provides stability and a near-native lipid environment to maintain membrane protein function (10).

SMALPs

Styrene maleic acid lipid particles (SMALPs) use styrene maleic acid (SMA) copolymers to solubilize membranes. The native lipid bilayer is then formed in a discoidal form and surrounded by an SMA copolymer belt (10). This allows the membrane protein to remain in its native membrane, preserving its structure and stability.

Surface plasmon resonance technology overview

Surface plasmon resonance (SPR) is an analytical method used to study molecular interactions. The target molecule or ligand is injected into the system and immobilized onto the SPR sensor chip. The sample or analyte— the prospective binding partner—is injected and binds to the target molecule or ligand. This binding causes a change in the refractive index and shifts the resonance angle. The interaction analysis profile is then recorded in real-time via a sensorgram (Fig 1).

Fig 1. shows a sensorgram. The bars below the curve indicate the solutions that pass over the sensor surface (12,13)

Sensorgrams can be used to determine key molecule characteristics, including:

• Rate of association and dissociation.
• Binding affinity: Calculated from the association and dissociation rates at different analyte concentrations.
• Analyte concentration: Determined from the sensorgram slope or the binding response after a fixed contact time.
• Binding specificity: Determined by comparing responses to different analytes.

Biacore™ system features

Biacore™ SPR systems are robust and reliable platforms for label-free interaction analysis using SPR technology. Designed to deliver high-quality, information-rich data, Biacore system helps answer critical questions about molecular binding—so your research is accelerated toward meaningful conclusions.

With advanced features for high-throughput and high-sensitivity analysis, Biacore instruments provide real-time evaluation of affinity, kinetics, epitope binning, and concentration across a broad molecular weight range, using minimal sample volumes.

Biacore Insight software provides unified instrument control and data evaluation, with optional application-specific extensions. It includes machine learning-based tools and seamless integration capabilities for automated workflows and cross-platform data management, for enhanced efficiency and reproducibility in your lab.

How does Biacore SPR technology measure membrane protein interactions?

Membrane protein-ligand interaction kinetics

Assessing interactions between membrane proteins and target molecules is complicated by the difficulty of extracting them from membranes while retaining native structure and function. Changes to membrane protein structure can impact their ability to bind, which can cause inaccurate results from biomolecular interaction investigations.

Despite these challenges, multiple studies have shown that Biacore SPR system can reliably measure membrane protein interactions across a range of preparation methods, including detergent solubilization, nanodiscs, amphipols, and SMALPs. These examples demonstrate that SPR can capture meaningful kinetic and affinity data even for unstable or conformationally sensitive protein targets.

Detergent-solubilized membrane protein

Harding et al. showed that Biacore SPR technology can generate specific binding data using a full-length, detergent‑solubilized GPCR as the analyte (14). In their preliminary study, the neurotensin (NT) ligand was immobilized on the sensor surface, and solubilized NTS‑1 GPCR was injected in solution. The interaction produced clear binding signals, indicating that the receptor retained sufficient functional structure to engage with its ligand.

Similarly, Boonen et al. also used Biacore SPR technology to investigate the binding kinetics of a detergent‑solubilized GPCR (15). In this study, the receptor was captured on the sensor chip via a histidine tag, and ten inhibitory monovalent nanobodies were injected as analytes. The work demonstrated a range of binding behaviors and kinetic profiles, showing that SPR can differentiate nanobodies with varying affinities (Fig 2).

Together, these studies illustrate that detergent‑solubilized membrane proteins can be effectively analyzed using SPR, provided they maintain adequate structural integrity and activity.

Fig 2. Sensorgrams of the ten monovalent nanobodies binding to the immobilized GPCR (15).

Nanodisc

Adamson and Watts used Biacore SPR system to determine the binding affinities of two G-proteins to the GPCR, NTS1 (16). The G-proteins were immobilized onto an SPR sensor chip, and NTS1 embedded in nanodiscs was injected. Using Biacore SPR system, they demonstrated the direct interaction of a GPCR in a nanodisc with the two G-proteins. The affinity constants showed high affinity for the receptor. Bocquet et al. similarly used a GPCR embedded in a nanodisc with Biacore SPR system to characterize the binding kinetics of small molecule binding (17). This study has particularly exciting implications for small-molecule drug discovery using SPR.

Biacore SPR use for detergent-free membrane-protein analysis

Membrane proteins can be stabilized using different methods, including detergent solubilization, nanodiscs, and SMALPs. The choice of method can alter protein stabilization and, consequently, protein function.

Biacore SPR technology can be used to compare membrane protein binding to the target molecule after the use of different stabilization techniques. Bocquet et al. used Biacore SPR technology to investigate how detergent-solubilized membrane protein receptors differed from the receptors isolated using nanodiscs (17). They demonstrated that the receptor possessed increased binding affinity with nanodiscs compared to the detergent micelles, and that receptor stability increased, as the nanodisc-incorporated receptor allowed SPR data acquisition on the same chip for up to three weeks without regeneration. The detergent-solubilized receptor lost activity after only 80 hours. This demonstrates that SPR can be used for detergent-free membrane protein analysis.

Analysis using Biacore SPR technology also shows the functionality of membrane proteins stabilized using novel methods. Sharma et al. prepared membrane protein SMALPs and confirmed functionality using SPR to assess the binding of specific antibodies (18). SPR technology was also used to assess the stability of the SMALPs in different buffers, demonstrating that the addition of Mg2+ resulted in SMALP disintegration, as confirmed by the absence of SPR binding data. Drulyte et al. used SPR to confirm that their PANX1 channel protein embedded in Salipro nanoparticles could bind to known inhibitors (Fig 3)(19). Salipro is a saposin-lipoprotein nanoparticle system where membrane proteins are stabilized in a lipid environment using saposin proteins as a scaffold for detergent-free membrane protein analysis using Biacore SPR technology (20).

Nanobody	ka (1/Ms)	kd (1/s)	KD (nM)	Biacore assay format
N15 (present study)	9.26E+05	1.98E-04	0.22	Biotin capture T2
N21 (present study)			48	Biotin capture T2

Fig 3. N15 and N21 binding kinetics and affinity to Salipro-T2 particles (In collaboration with Salipro Biotech).

Comparing binding affinities and functional responses across formats

Membrane protein stability depends on the environment in which it is solubilized. Close-to native environments usually provide optimal stability and maintain the protein in its native conformation. Environments or formats affecting the stability and conformation of membrane proteins can have a significant impact on functional responses.

Native vs. denatured conditions

In an investigation into the CXCR4 GPCR, a receptor associated with several pathologies (including cancer and HIV), Boonen et al. used Biacore SPR technology to determine CXCR4 stability in different buffers. CXCR4 was only able to bind to the monoclonal antibody when diluted in the regular buffer, and not when in a buffer supplemented with Triton X-100. This demonstrates that the antibody fails to bind when CXCR4 is not in its stable conformation (Fig 4)(15). Navratilova et al. used Biacore SPR technology to assess GPCR stability in different solubilization conditions by using conformation-dependent monoclonal antibodies. These antibodies only bind when the receptor is in its native conformation, providing a method to screen solubilization conditions (21).

Fig 4. Sensorgram of CXCR4 binding to the monoclonal antibody in regular buffer (blue) and the Triton X-100 buffer (black) (15).

Comparing transmembrane to soluble proteins

To investigate the interaction between anti-TNF agents and transmembrane TNF-α, Ogura et al. used Biacore SPR system to assess binding responses (22). Transmembrane TNF-α was not solubilized for this work. Instead, whole Jurkat cells expressing transmembrane TNF-α were injected into the Biacore system, where anti-TNF agents had been captured onto an SPR sensor chip. Using these whole cells, they successfully demonstrated clear binding of the transmembrane TNF-α to the anti-TNF agents.

Comparing salt concentrations

Schillinger et al. used Biacore SPR technology to compare the binding of two homologous proteins to lipid vesicles. One homologue is intracellularly located and the other can be found in the membrane (23). As part of this work, they investigated how the two homologues reacted to different salt concentrations. The binding of the vesicles to the membrane-associated homologue (PR3) was shown to be more resistant to increased salt concentrations. The intracellular homologue (HNE) developed unstable binding at higher salt concentrations and partially dissociated from the vesicles.

Comparing immobilization procedures

In SPR, the site of binding molecules onto the SPR sensor chip and their orientation can affect binding to the target molecule. To assess how kinetic parameters differ depending on the immobilization procedure, Bocquet et al. immobilized their nanodiscs either directly or via a tag on the GPCR protein (17). They did not find any significant differences in association or dissociation rates between the different immobilization strategies.

Screening and validation of membrane protein-targeting compounds

The successful development of different techniques for using stable, close-to-native membrane proteins enables the use of Biacore SPR system for screening membrane protein-targeting compounds. This holds significant potential for drug screening to increase successful development of drugs for pathological membrane proteins.

Biacore SPR system was used by Bonvicini et al. to measure binding affinity to a membrane protein used to transport large drug molecules across the blood-brain barrier, as affinity influences transport efficiency (24). They demonstrated that the three antibodies being tested showed high affinity for membrane protein receptors. They also showed that the measured affinities altered depending on experiment set-up (i.e., which species was immobilized and which injected). This highlights the importance of evaluating assay parameters when comparing kinetics of protein binding.

Shepherd et al. used Biacore SPR system to screen similar libraries of drug-like chemical fragments and small molecules to identify novel binders to the GPCR, A_2AR, a potential drug target in tumors (25). SPR was sufficiently sensitive to detect fragments as small as 140 Da with affinities as low as 3.6 μM. From the initial fragment screen, seventeen fragments were screened against other receptors in the family to assess selectivity to A_2AR. Two fragments were identified that had selectivity for A_2AR (Fig 5). Huber et al. also used SPR to screen fragment libraries for binding to the GPCR potential drug target, NTS1 (26). From over 6000 fragments, SPR identified 44 hits. In both studies, SPR was crucial to eliminate nonbinding molecules during screening and identify promising fragments for further exploration.

Fig 5. Sensorgrams demonstrate the ability of Biacore SPR technology to assess the kinetics of fragment binding to the GPCR with a wide range of fragment sizes and affinities. Data courtesy: Hopkins/Navratilova lab, University of Dundee, UK. Cytiva thanks Dr. Iva Hopkins Navratilova and Prof. Andrew Hopkins for a fruitful collaboration, sharing assay conditions and results.

The advantages of using SPR to study membrane proteins

Membrane proteins are a notoriously difficult class of proteins to analyze due to their instability, tendency to aggregate, and naturally low abundance. The development of novel purification techniques, including detergent solubilization, nanodiscs, and SMALPs enable the analysis of protein binding kinetics using SPR, with the potential to aid future drug discovery. Key advantages of using Biacore SPR technology in membrane protein research include:

Versatile assay design and experimental flexibility

They allow researchers to investigate a wide range of mechanistic questions. Membrane proteins can have complex biomolecular interactions. They bind with extracellular and intercellular ligands, co-factors, and signaling molecules. The flexibility to design assay formats in which the membrane protein can be used as either ligand or analyte, allows these complex interactions to be resolved in creative ways. This can include:

• Capturing membrane protein to screen ligands against the orthosteric binding site
• Running in competition format with A-B-A injections to detect allosteric binders,
• Measuring complex formation (e.g., GPCR:G-protein complex) using poly-inject sequences

They allow researchers to investigate a wide range of mechanistic questions. Membrane proteins can have complex biomolecular interactions. They bind with extracellular and intercellular ligands, co-factors, and signaling molecules. The flexibility to design assay formats with the membrane protein as the ligand or analyte allows these complex interactions to be resolved in creative ways. This can include:

• Capturing membrane protein to screen ligands against the orthosteric binding
• Capturing membrane protein to screen ligands against the orthosteric bindingsite
• Running in competition format with A-B-A injections to detect allosteric binders
• Measuring complex formation (e.g., GPCR:G-protein complex) using poly-inject sequences

These capabilities help researchers resolve interaction mechanisms that may be difficult to study using other biophysical methods.

Compatibility with multiple solubilization strategies

Published studies have shown that SPR can be used effectively with membrane proteins prepared using a variety of stabilization approaches. This includes detergent‑solubilized receptors as well as proteins incorporated into nanodiscs or SMALPs, which can better preserve native‑like structure. Different immobilization strategies can also be applied to determine how capture method or surface orientation affects binding behavior.

This flexibility allows researchers to identify preparation conditions that maintain functional activity and produce the most reliable kinetic data.

Biacore system has high reproducibility in low-expression systems

Membrane proteins are naturally expressed at low concentrations, so it's difficult to obtain sufficient protein for many analytical methods. Biacore SPR system is highly sensitive and only requires small sample volumes. For example, the Biacore 8 series system can use less than 1 μg of sample to capture a 30 kDa GPCR on an NTA chip.

Biacore system uses label-free detection

Unlike other common techniques for analyzing biomolecular interactions, including microscale thermophoresis, Biacore SPR technology does not require the use of molecular labels (29). The binding of such labels to membrane proteins or their target ligands can alter the conformation of the proteins, potentially resulting in altered binding kinetics (30). The label-free nature of Biacore SPR technology ensures that proteins are not affected by labels and retain their native function, resulting in accurate and reproducible results.

Biacore system provides high sensitivity for weak interactions

Low-affinity biomolecular interactions can be difficult to detect using traditional techniques. Biacore SPR system is highly sensitive and allows for reliable detection of interactions between potential drugs and their target membrane proteins.

Biacore system supports high‑throughput screening

Researchers require high-throughput determination of binding characteristics, particularly when screening a library with thousands of potential binders. Unlike many other methods for characterizing biomolecular interactions, such as isothermal titration calorimetry, Biacore SPR assays are high-throughput for rapid compound screening (31, 32).

Future outlook

Advances in Biacore SPR system has continued at a steady rate over the past decade. The Biacore 8 series system offers its highest ever throughput and built-in sample capacity (a maximal capacity of over 4600 samples) and sensitivity (10^-6 to 0.5 s^-1) (33). Biacore 1 series system is designed for increased assay flexibility and reduced complexity. Sensor chip optimization also continues, with an increasing number of chips available to cover a wide range of surface modifications and applications (Fig 6).

Fig 6. (A) Schematic representation of the structure of an SPR sensor chip. (B-C) Selection of commercially available sensor chips from Cytiva.

Incorporation of artificial intelligence (AI) into Biacore SPR system has the potential to transform how researchers use this technology. SPR produces increasingly large datasets, which require experience and time to analyze. AI and machine learning can be used to optimize and enhance data interpretation (34). This will support faster data analysis, provide rapid data insights, and make SPR more accessible. Biacore Insight software is already incorporated into the latest Biacore system. The software provides methods and templates to get researchers started regardless of experience level (34). Optional machine learning software extensions, such as Biacore Intelligent Analysis™ software, are available to assist researchers with benefits such as improved flexibility, streamlined workflows, and enhanced reproducibility to maximize scientific discoveries using SPR.

Membrane protein research is moving toward increasingly complex targets and experimental conditions. Emerging trends include the study of multi-protein complexes, intrinsically disordered regions, and dynamic conformational states under physiologically relevant environments. These directions aim to deepen understanding of signaling pathways, druggable pockets, and mechanisms of action for challenging targets such as GPCRs and ion channels.

Biacore SPR system, with its existing capabilities, is well-positioned to support these developments:

• Real-time kinetic analysis for complex interactions
  Current Biacore platforms provide high-resolution kinetic data. Researchers can capture rapid association and dissociation events and transient interactions that are critical to understanding membrane protein function.
• Compatibility with native-like formats
  Biacore SPR assays can accommodate membrane proteins stabilized in nanodiscs, SMALPs, or detergent micelles. This allows researchers to study interactions in environments that preserve native conformation and activity.
• High sensitivity for low-abundance targets
  Membrane proteins are often expressed at low levels. Biacore system requires minimal sample quantities and is well-suited for scarce or difficult to purify targets.
• Versatile assay design for mechanistic insights
  Researchers can design interaction formats to explore orthosteric and allosteric binding, competitive interactions, and multi-component complexes providing a deeper understanding of receptor activation and signaling.
• Integration with digital workflows
  Biacore software supports automated data evaluation and connectivity with electronic lab notebooks. The software streamlines analysis and enhances reproducibility in collaborative research environments.

As the field advances toward more physiologically relevant and structurally complex studies, Biacore SPR system remains a powerful tool for generating robust, reproducible data that informs drug discovery and fundamental biology.

Conclusion

Biacore SPR system is an essential tool in the analysis of membrane proteins. The versatility and sensitivity allow membrane protein-ligand interactions to be assessed, membrane protein functionality to be investigated following solubilization, functional responses to be compared across different formats and experimental setups, and large-scale screenings for the identification of potential drug candidates. Biacore SPR system can evaluate low volume samples, so membrane proteins that are difficult to purify or have naturally low abundance can be assessed. High reproducibility allows researchers to produce precise answers to a wide variety of questions.

FAQs

1. What is SPR?
   Surface plasmon resonance (SPR) is a label-free technique used to study biomolecular interactions in real time. It detects changes in mass near a sensor surface when molecules bind, providing insights into binding kinetics, affinity measurements, and concentration. SPR is widely used in drug screening and discovery and protein characterization due to its sensitivity and versatility.
2. Why use SPR for membrane protein interactions?
   SPR is label‑free and real‑time, delivering kinetics (k_on/k_off), affinity (K_D), and specificity with low sample consumption, well suited for scarce or fragile membrane targets.
3. Which sample formats work best in SPR: detergents, nanodiscs, SMALPs, or Salipro?
   All can be compatible. Nanodiscs and SMALPs maintain a lipid environment and often preserve function better than detergents. Salipro DirectMX enables one‑step extraction into saposin nanoparticles ready for SPR. Choice depends on target stability and assay goals.
4. Do nanodiscs complicate surface preparation for SPR?
   Not necessarily. Approaches include His‑tag capture (NTA chips), biotin–streptavidin capture, or even anti‑MSP capture antibodies to orient and stabilize nanodisc‑reconstituted receptors on the sensor surface.
5. How do I decide between a detergent micelle and a membrane mimetic?
   If the receptor is stable and active in a mild detergent (e.g., LMNG), micelles can work. If activity or stability drops, consider nanodiscs, SMALPs, or Salipro, which better preserve native lipid interactions. Pilot binding and activity tests usually decide it.
6. Can Biacore system handle small molecules for GPCRs and transporters?
   Yes. For fragments and small molecules, ensure rigorous DMSO solvent correction, good reference surfaces, and adequate mass‑transport control. Biacore methods and templates support high‑quality fragment screens.
7. Can SPR work with intact cells or vesicles?
   Whole‑cell SPR has been shown by flowing cell suspensions over immobilized capture molecules (e.g., anti‑TNF reagents vs. mTNF‑α on Jurkat cells), enabling interaction assessment in a near‑native context.

 

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