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 groupOrder productsSpacer Arm (Å)Cleavable?Water-soluble?Membrane-permeable?Reversible?
NHS esterDSG7.7N/ANoYesNo
DSS  11.4N/ANoYesNo
BS311.4N/AYesNoNo
TSAT (trifunctional)4.2N/ANoNoNo
BS(PEG)521.7N/AYesNoNo
BS(PEG)9  35.8N/AYesNoNo
DSP  12.0ThiolsNoYesNo
DTSSP  12.0ThiolsYesNoNo
DST  6.4PeriodateYesYesNo
BSOCOES13.0BaseNoYesNo
EGS  16.1HydoxylamineNoYesYes
Sulfo-EGS  16.1HydoxylamineYesNoYes
ImidoesterDMA8.6  N/AYesYesYes
DMP9.2N/AYesYesYes
DMS11.0N/AYesYesYes
DTBP11.9ThiolYesYesNo
DifluoroDFDNB3.0N/ANoYesYes

Sulfhydryl-to-sulfhydryl

Sulfhydryl -to-Sulfhydryl CrosslinkersOrder productSpacer Arm (Å)Cleavable?Water-soluble?Membrane permeable?
NHS-Haloacetyl CrosslinkersSIA1.5N/ANoYes
SBAP6.2 N/ANoYes
SIAB10.6 N/ANoYes
Sulfo-SIAB10.6 N/AYesNo
NHS-MaleimideAMAS4.4N/ANoYes
BMPS5.9N/ANoYes
GMBS7.3N/ANoYes
Sulfo-GMBS7.3N/AYesNo
MBS7.3N/ANoYes
Sulfo-MBS7.3N/AYesNo
SMCC8.3N/ANoYes
Sulfo-SMCC8.3N/AYesNo
EMCS9.4N/ANoYes
Sulfo-EMCS9.4N/AYesNo
SMPB11.6N/ANoYes
Sulfo-SMPB11.6N/AYesNo
SMPH14.2N/ANoYes
LC-SMCC16.2N/ANoYes
Sulfo-KMUS16.3N/ANoYes
NHS-Pyridyldithiol CrosslinkersSPDP6.8ThiolNoYes
LC-SPDP15.7ThiolNoYes
Sulfo-LC-SPDP15.7ThiolYesNo
SMPT11.2ThiolNoYes
PEG4-SPDP25.7ThiolYesNo
PEG12-SPDP54.1ThiolYesNo

Amine-to-sulfhydryl

Reactive groupOrder productSpacer Arm (Å)Cleavable?Water-soluble?Membrane permeable?
NHS-HaloacetylSIA1.5N/ANoYes
SBAP6.2 N/ANoYes
SIAB10.6 N/ANoYes
Sulfo-SIAB10.6 N/AYesNo
NHS-MaleimideAMAS4.4N/ANoYes
BMPS5.9N/ANoYes
GMBS7.3N/ANoYes
Sulfo-GMBS7.3N/AYesNo
MBS7.3N/ANoYes
Sulfo-MBS7.3N/AYesNo
SMCC8.3N/ANoYes
Sulfo-SMCC8.3N/AYesNo
EMCS9.4N/ANoYes
Sulfo-EMCS9.4N/AYesNo
SMPB11.6N/ANoYes
Sulfo-SMPB11.6N/AYesNo
SMPH14.2N/ANoYes
LC-SMCC16.2N/ANoYes
Sulfo-KMUS16.3N/ANoYes
NHS-Pyridyldithiol CrosslinkersSPDP6.8ThiolNoYes
LC-SPDP15.7ThiolNoYes
Sulfo-LC-SPDP15.7ThiolYesNo
SMPT11.2ThiolNoYes
PEG4-SPDP25.7ThiolYesNo
PEG12-SPDP54.1ThiolYesNo

Carboxyl-to-amine

Reactive groupOrder productCleavable ?Water-soluble?Membrane permeable?
Carbodiimide / NHS esterDCCNoNoYes
EDCNoYesNo
NHS  NoNoYes
Sulfo-NHSNoYesNo

Sulfhydryl-to-carboxyl

Reactive groupOrder productSpacer Arm (Å)Cleavable?Water-soluble?Membrane permeable?
Maleimide / hydrazide   BMPH8.1A  ShortNoYesYes
EMCH11.8A MidNoYesYes
MPBH17.9A LongNoNoYes
KMUH19.0A LongNoNoYes
Pyridyldithiol / hydrazidePDPH9.2A ShortThiolsYesYes

Photoreactive

Reactive groupOrder productSpacer Arm (Å)Cleavable by?Water-soluble ?Membrane permeable?
NHS ester/ aryl azideANB-NOS7.7 ShortNoNoNo
Sulfo-SANPAH18.2 LongNoYesNo
NHS ester/ diazirineSDA3.9 ShortNoNoYes
Sulfo-SDA3.9 ShortNoYesNo
LC-SDA  12.5 MidNoNoYes
Sulfo-LC-SDA12.5 MidNoYesNo
SDAD  13.5 MidThiolsNoYes
Sulfo-SDAD13.5 MidThiolsYesNo

Chemoselective

Reactive groupOrder productSpacer Arm (Å)Cleavable by?Water-soluble ?Membrane permeable?
NHS ester/ aryl azideNHS-Azide2.5NoNoND*
NHS-PEG4-Azide18.9NoNoND*
NHS ester/ diazirineNHS-Phosphine5.4NoNoND*

* Not determined

Amine-to-amine

Reactive groupOrder productsSpacer Arm (Å)Cleavable?Water-soluble?Membrane-permeable?Reversible?
NHS esterDSG7.7N/ANoYesNo
DSS  11.4N/ANoYesNo
BS311.4N/AYesNoNo
TSAT (trifunctional)4.2N/ANoNoNo
BS(PEG)521.7N/AYesNoNo
BS(PEG)9  35.8N/AYesNoNo
DSP  12.0ThiolsNoYesNo
DTSSP  12.0ThiolsYesNoNo
DST  6.4PeriodateYesYesNo
BSOCOES13.0BaseNoYesNo
EGS  16.1HydoxylamineNoYesYes
Sulfo-EGS  16.1HydoxylamineYesNoYes
ImidoesterDMA8.6  N/AYesYesYes
DMP9.2N/AYesYesYes
DMS11.0N/AYesYesYes
DTBP11.9ThiolYesYesNo
DifluoroDFDNB3.0N/ANoYesYes

Sulfhydryl-to-sulfhydryl

Sulfhydryl -to-Sulfhydryl CrosslinkersOrder productSpacer Arm (Å)Cleavable?Water-soluble?Membrane permeable?
NHS-Haloacetyl CrosslinkersSIA1.5N/ANoYes
SBAP6.2 N/ANoYes
SIAB10.6 N/ANoYes
Sulfo-SIAB10.6 N/AYesNo
NHS-MaleimideAMAS4.4N/ANoYes
BMPS5.9N/ANoYes
GMBS7.3N/ANoYes
Sulfo-GMBS7.3N/AYesNo
MBS7.3N/ANoYes
Sulfo-MBS7.3N/AYesNo
SMCC8.3N/ANoYes
Sulfo-SMCC8.3N/AYesNo
EMCS9.4N/ANoYes
Sulfo-EMCS9.4N/AYesNo
SMPB11.6N/ANoYes
Sulfo-SMPB11.6N/AYesNo
SMPH14.2N/ANoYes
LC-SMCC16.2N/ANoYes
Sulfo-KMUS16.3N/ANoYes
NHS-Pyridyldithiol CrosslinkersSPDP6.8ThiolNoYes
LC-SPDP15.7ThiolNoYes
Sulfo-LC-SPDP15.7ThiolYesNo
SMPT11.2ThiolNoYes
PEG4-SPDP25.7ThiolYesNo
PEG12-SPDP54.1ThiolYesNo

Amine-to-sulfhydryl

Reactive groupOrder productSpacer Arm (Å)Cleavable?Water-soluble?Membrane permeable?
NHS-HaloacetylSIA1.5N/ANoYes
SBAP6.2 N/ANoYes
SIAB10.6 N/ANoYes
Sulfo-SIAB10.6 N/AYesNo
NHS-MaleimideAMAS4.4N/ANoYes
BMPS5.9N/ANoYes
GMBS7.3N/ANoYes
Sulfo-GMBS7.3N/AYesNo
MBS7.3N/ANoYes
Sulfo-MBS7.3N/AYesNo
SMCC8.3N/ANoYes
Sulfo-SMCC8.3N/AYesNo
EMCS9.4N/ANoYes
Sulfo-EMCS9.4N/AYesNo
SMPB11.6N/ANoYes
Sulfo-SMPB11.6N/AYesNo
SMPH14.2N/ANoYes
LC-SMCC16.2N/ANoYes
Sulfo-KMUS16.3N/ANoYes
NHS-Pyridyldithiol CrosslinkersSPDP6.8ThiolNoYes
LC-SPDP15.7ThiolNoYes
Sulfo-LC-SPDP15.7ThiolYesNo
SMPT11.2ThiolNoYes
PEG4-SPDP25.7ThiolYesNo
PEG12-SPDP54.1ThiolYesNo

Carboxyl-to-amine

Reactive groupOrder productCleavable ?Water-soluble?Membrane permeable?
Carbodiimide / NHS esterDCCNoNoYes
EDCNoYesNo
NHS  NoNoYes
Sulfo-NHSNoYesNo

Sulfhydryl-to-carboxyl

Reactive groupOrder productSpacer Arm (Å)Cleavable?Water-soluble?Membrane permeable?
Maleimide / hydrazide   BMPH8.1A  ShortNoYesYes
EMCH11.8A MidNoYesYes
MPBH17.9A LongNoNoYes
KMUH19.0A LongNoNoYes
Pyridyldithiol / hydrazidePDPH9.2A ShortThiolsYesYes

Photoreactive

Reactive groupOrder productSpacer Arm (Å)Cleavable by?Water-soluble ?Membrane permeable?
NHS ester/ aryl azideANB-NOS7.7 ShortNoNoNo
Sulfo-SANPAH18.2 LongNoYesNo
NHS ester/ diazirineSDA3.9 ShortNoNoYes
Sulfo-SDA3.9 ShortNoYesNo
LC-SDA  12.5 MidNoNoYes
Sulfo-LC-SDA12.5 MidNoYesNo
SDAD  13.5 MidThiolsNoYes
Sulfo-SDAD13.5 MidThiolsYesNo

Chemoselective

Reactive groupOrder productSpacer Arm (Å)Cleavable by?Water-soluble ?Membrane permeable?
NHS ester/ aryl azideNHS-Azide2.5NoNoND*
NHS-PEG4-Azide18.9NoNoND*
NHS ester/ diazirineNHS-Phosphine5.4NoNoND*

* Not determined

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