Protein Crosslinking

Crosslinkers contain reactive ends to specific functional groups, such as primary amines and sulfhydryls on proteins and antibodies, enabling the covalent joining of or two or more biomolecules. Homobifunctional crosslinkers have the same reactive chemistry at both ends and heterobifunctional have different chemistries at each end. PEGylated crosslinkers have enhanced solubility, increased stability, reduced aggregation, and reduced immunogenicity. Use our crosslinker selection tool to find the optimal reagent for your protein function or interaction application, or access our helpful Bioconjugation Technical Handbook to help improve your crosslinking results.

Crosslinker Selection Tool

Learn more about crosslinking chemistries
Learn more about unreactive crosslinker and small molecule removal

Choose the right crosslinker based on reactive chemistry

Amine-to-amine

Reactive group Order products Spacer Arm (Å) Cleavable? Water-soluble? Membrane-permeable? Reversible?
NHS ester DSG 7.7 N/A No Yes No
DSS   11.4 N/A No Yes No
BS3 11.4 N/A Yes No No
TSAT (trifunctional) 4.2 N/A No No No
BS(PEG)5 21.7 N/A Yes No No
BS(PEG)9   35.8 N/A Yes No No
DSP   12.0 Thiols No Yes No
DTSSP   12.0 Thiols Yes No No
DST   6.4 Periodate Yes Yes No
BSOCOES 13.0 Base No Yes No
EGS   16.1 Hydoxylamine No Yes Yes
Sulfo-EGS   16.1 Hydoxylamine Yes No Yes
Imidoester DMA 8.6   N/A Yes Yes Yes
DMP 9.2 N/A Yes Yes Yes
DMS 11.0 N/A Yes Yes Yes
DTBP 11.9 Thiol Yes Yes No
Difluoro DFDNB 3.0 N/A No Yes Yes

Sulfhydryl-to-sulfhydryl

Sulfhydryl -to-Sulfhydryl Crosslinkers Order product Spacer Arm (Å) Cleavable? Water-soluble? Membrane permeable?
NHS-Haloacetyl Crosslinkers SIA 1.5 N/A No Yes
SBAP 6.2  N/A No Yes
SIAB 10.6  N/A No Yes
Sulfo-SIAB 10.6  N/A Yes No
NHS-Maleimide AMAS 4.4 N/A No Yes
BMPS 5.9 N/A No Yes
GMBS 7.3 N/A No Yes
Sulfo-GMBS 7.3 N/A Yes No
MBS 7.3 N/A No Yes
Sulfo-MBS 7.3 N/A Yes No
SMCC 8.3 N/A No Yes
Sulfo-SMCC 8.3 N/A Yes No
EMCS 9.4 N/A No Yes
Sulfo-EMCS 9.4 N/A Yes No
SMPB 11.6 N/A No Yes
Sulfo-SMPB 11.6 N/A Yes No
SMPH 14.2 N/A No Yes
LC-SMCC 16.2 N/A No Yes
Sulfo-KMUS 16.3 N/A No Yes
NHS-Pyridyldithiol Crosslinkers SPDP 6.8 Thiol No Yes
LC-SPDP 15.7 Thiol No Yes
Sulfo-LC-SPDP 15.7 Thiol Yes No
SMPT 11.2 Thiol No Yes
PEG4-SPDP 25.7 Thiol Yes No
PEG12-SPDP 54.1 Thiol Yes No

Amine-to-sulfhydryl

Reactive group Order product Spacer Arm (Å) Cleavable? Water-soluble? Membrane permeable?
NHS-Haloacetyl SIA 1.5 N/A No Yes
SBAP 6.2  N/A No Yes
SIAB 10.6  N/A No Yes
Sulfo-SIAB 10.6  N/A Yes No
NHS-Maleimide AMAS 4.4 N/A No Yes
BMPS 5.9 N/A No Yes
GMBS 7.3 N/A No Yes
Sulfo-GMBS 7.3 N/A Yes No
MBS 7.3 N/A No Yes
Sulfo-MBS 7.3 N/A Yes No
SMCC 8.3 N/A No Yes
Sulfo-SMCC 8.3 N/A Yes No
EMCS 9.4 N/A No Yes
Sulfo-EMCS 9.4 N/A Yes No
SMPB 11.6 N/A No Yes
Sulfo-SMPB 11.6 N/A Yes No
SMPH 14.2 N/A No Yes
LC-SMCC 16.2 N/A No Yes
Sulfo-KMUS 16.3 N/A No Yes
NHS-Pyridyldithiol Crosslinkers SPDP 6.8 Thiol No Yes
LC-SPDP 15.7 Thiol No Yes
Sulfo-LC-SPDP 15.7 Thiol Yes No
SMPT 11.2 Thiol No Yes
PEG4-SPDP 25.7 Thiol Yes No
PEG12-SPDP 54.1 Thiol Yes No

Carboxyl-to-amine

Reactive group Order product Cleavable ? Water-soluble? Membrane permeable?
Carbodiimide / NHS ester DCC No No Yes
EDC No Yes No
NHS   No No Yes
Sulfo-NHS No Yes No

Sulfhydryl-to-carboxyl

Reactive group Order product Spacer Arm (Å) Cleavable? Water-soluble? Membrane permeable?
Maleimide / hydrazide    BMPH 8.1A  Short No Yes Yes
EMCH 11.8A Mid No Yes Yes
MPBH 17.9A Long No No Yes
KMUH 19.0A Long No No Yes
Pyridyldithiol / hydrazide PDPH 9.2A Short Thiols Yes Yes

Photoreactive

Reactive group Order product Spacer Arm (Å) Cleavable by? Water-soluble ? Membrane permeable?
NHS ester/ aryl azide ANB-NOS 7.7 Short No No No
Sulfo-SANPAH 18.2 Long No Yes No
NHS ester/ diazirine SDA 3.9 Short No No Yes
Sulfo-SDA 3.9 Short No Yes No
LC-SDA   12.5 Mid No No Yes
Sulfo-LC-SDA 12.5 Mid No Yes No
SDAD   13.5 Mid Thiols No Yes
Sulfo-SDAD 13.5 Mid Thiols Yes No

Chemoselective

Reactive group Order product Spacer Arm (Å) Cleavable by? Water-soluble ? Membrane permeable?
NHS ester/ aryl azide NHS-Azide 2.5 No No ND*
NHS-PEG4-Azide 18.9 No No ND*
NHS ester/ diazirine NHS-Phosphine 5.4 No No ND*

* Not determined

Homobifunctional

Amine-to-amine

Reactive group Order products Spacer Arm (Å) Cleavable? Water-soluble? Membrane-permeable? Reversible?
NHS ester DSG 7.7 N/A No Yes No
DSS   11.4 N/A No Yes No
BS3 11.4 N/A Yes No No
TSAT (trifunctional) 4.2 N/A No No No
BS(PEG)5 21.7 N/A Yes No No
BS(PEG)9   35.8 N/A Yes No No
DSP   12.0 Thiols No Yes No
DTSSP   12.0 Thiols Yes No No
DST   6.4 Periodate Yes Yes No
BSOCOES 13.0 Base No Yes No
EGS   16.1 Hydoxylamine No Yes Yes
Sulfo-EGS   16.1 Hydoxylamine Yes No Yes
Imidoester DMA 8.6   N/A Yes Yes Yes
DMP 9.2 N/A Yes Yes Yes
DMS 11.0 N/A Yes Yes Yes
DTBP 11.9 Thiol Yes Yes No
Difluoro DFDNB 3.0 N/A No Yes Yes

Sulfhydryl-to-sulfhydryl

Sulfhydryl -to-Sulfhydryl Crosslinkers Order product Spacer Arm (Å) Cleavable? Water-soluble? Membrane permeable?
NHS-Haloacetyl Crosslinkers SIA 1.5 N/A No Yes
SBAP 6.2  N/A No Yes
SIAB 10.6  N/A No Yes
Sulfo-SIAB 10.6  N/A Yes No
NHS-Maleimide AMAS 4.4 N/A No Yes
BMPS 5.9 N/A No Yes
GMBS 7.3 N/A No Yes
Sulfo-GMBS 7.3 N/A Yes No
MBS 7.3 N/A No Yes
Sulfo-MBS 7.3 N/A Yes No
SMCC 8.3 N/A No Yes
Sulfo-SMCC 8.3 N/A Yes No
EMCS 9.4 N/A No Yes
Sulfo-EMCS 9.4 N/A Yes No
SMPB 11.6 N/A No Yes
Sulfo-SMPB 11.6 N/A Yes No
SMPH 14.2 N/A No Yes
LC-SMCC 16.2 N/A No Yes
Sulfo-KMUS 16.3 N/A No Yes
NHS-Pyridyldithiol Crosslinkers SPDP 6.8 Thiol No Yes
LC-SPDP 15.7 Thiol No Yes
Sulfo-LC-SPDP 15.7 Thiol Yes No
SMPT 11.2 Thiol No Yes
PEG4-SPDP 25.7 Thiol Yes No
PEG12-SPDP 54.1 Thiol Yes No
Heterobifunctional

Amine-to-sulfhydryl

Reactive group Order product Spacer Arm (Å) Cleavable? Water-soluble? Membrane permeable?
NHS-Haloacetyl SIA 1.5 N/A No Yes
SBAP 6.2  N/A No Yes
SIAB 10.6  N/A No Yes
Sulfo-SIAB 10.6  N/A Yes No
NHS-Maleimide AMAS 4.4 N/A No Yes
BMPS 5.9 N/A No Yes
GMBS 7.3 N/A No Yes
Sulfo-GMBS 7.3 N/A Yes No
MBS 7.3 N/A No Yes
Sulfo-MBS 7.3 N/A Yes No
SMCC 8.3 N/A No Yes
Sulfo-SMCC 8.3 N/A Yes No
EMCS 9.4 N/A No Yes
Sulfo-EMCS 9.4 N/A Yes No
SMPB 11.6 N/A No Yes
Sulfo-SMPB 11.6 N/A Yes No
SMPH 14.2 N/A No Yes
LC-SMCC 16.2 N/A No Yes
Sulfo-KMUS 16.3 N/A No Yes
NHS-Pyridyldithiol Crosslinkers SPDP 6.8 Thiol No Yes
LC-SPDP 15.7 Thiol No Yes
Sulfo-LC-SPDP 15.7 Thiol Yes No
SMPT 11.2 Thiol No Yes
PEG4-SPDP 25.7 Thiol Yes No
PEG12-SPDP 54.1 Thiol Yes No

Carboxyl-to-amine

Reactive group Order product Cleavable ? Water-soluble? Membrane permeable?
Carbodiimide / NHS ester DCC No No Yes
EDC No Yes No
NHS   No No Yes
Sulfo-NHS No Yes No

Sulfhydryl-to-carboxyl

Reactive group Order product Spacer Arm (Å) Cleavable? Water-soluble? Membrane permeable?
Maleimide / hydrazide    BMPH 8.1A  Short No Yes Yes
EMCH 11.8A Mid No Yes Yes
MPBH 17.9A Long No No Yes
KMUH 19.0A Long No No Yes
Pyridyldithiol / hydrazide PDPH 9.2A Short Thiols Yes Yes

Photoreactive

Reactive group Order product Spacer Arm (Å) Cleavable by? Water-soluble ? Membrane permeable?
NHS ester/ aryl azide ANB-NOS 7.7 Short No No No
Sulfo-SANPAH 18.2 Long No Yes No
NHS ester/ diazirine SDA 3.9 Short No No Yes
Sulfo-SDA 3.9 Short No Yes No
LC-SDA   12.5 Mid No No Yes
Sulfo-LC-SDA 12.5 Mid No Yes No
SDAD   13.5 Mid Thiols No Yes
Sulfo-SDAD 13.5 Mid Thiols Yes No

Chemoselective

Reactive group Order product Spacer Arm (Å) Cleavable by? Water-soluble ? Membrane permeable?
NHS ester/ aryl azide NHS-Azide 2.5 No No ND*
NHS-PEG4-Azide 18.9 No No ND*
NHS ester/ diazirine NHS-Phosphine 5.4 No No ND*

* Not determined

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Resources

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