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Size Exclusion Chromatography (SEC): A Critical Tool for Protein Purification

Written by The Protein Man | May 5, 2025 7:45:49 PM

Size Exclusion Chromatography (SEC) remains a cornerstone method for protein purification, valued for its ability to deliver high-purity samples with minimal loss of biological activity. From structural analysis to functional studies and therapeutic development, the purity of protein preparations directly impacts experimental outcomes.

It’s a simple, baseline reality: Producing high-quality protein samples is critical to accurate and reproducible scientific research. Poor-quality protein samples yield inconsistent experimental results, making interpreting and replicating data difficult. Ultimately, a poor sample undermines scientific research.

Principles of the SEC

Size Exclusion Chromatography, or gel filtration chromatography, separates proteins based on their molecular size as they pass through a column filled with porous beads. Proteins navigate through the column based on size: larger molecules elute faster as they bypass the pores, while smaller proteins enter the pores and take a longer path to elute.
Size exclusion chromatography uses resins composed of agarose, polyacrylamide, or dextran polymer beads. Unlike other chromatographic resins, size exclusion resins do not directly bind target molecules. Separation of biomolecules occurs when particles of varying sizes are included or excluded from the pores in the matrix. Purifying proteins involves removing unwanted contaminants like nucleic acids, lipids, and other proteins. SEC is a critical final step to ensure the target protein isolates in its pure, biologically active form. SEC stationary phases have specified fractionation ranges that outline the molecular weight ranges that a given matrix can separate. Small biomolecules, like peptides, need size exclusion resins with low fractionation ranges. Larger particles, like antibodies, require stationary phases with higher fractionation ranges. 

Key Benefits That Make the SEC Indispensable

SEC provides the native state of proteins in high resolution, allowing researchers to distinguish between closely related species, such as monomers and aggregates. SEC's flexibility enables its use across a broad range of molecular weights, from small peptides to large complexes, allowing it to be scaled from small analytical applications to large preparative purifications without compromising performance.

Due to its reliability, versatility, and non-denaturing separation process, SEC is one of the cornerstone techniques in protein research, making it an ideal choice where high purity and intact protein structure are required. For example, in:

  • Structural biology studies
  • Enzyme kinetics and mechanistic studies
  • Protein-protein and protein-ligand interaction studies
  • Drug discovery and development
  • Therapeutic protein production
  • Functional assays
  • Proteomics research

SEC enables the researchers to rely on critical tasks such as:

  • Analyzing protein aggregation and oligomerization by distinguishing monomeric antibodies from aggregates in therapeutic protein development.
  • Estimating molecular weight from retention times is often employed in characterizing novel recombinant proteins.
  • Studying protein complexes and ligand binding, allowing for the analysis of enzyme-substrate interactions or antibody-antigen complexes.
  • Performing buffer exchange and desalting steps, enabling the preparation of proteins for crystallization trials or downstream functional assays.

Best Practices for Successful Size Exclusion Chromatography

To ensure accurate results while using SEC, researchers must focus on the following parameters: 

  • Choose the right column matrix and pore size: Selecting a column with an appropriate pore size ensures that the target protein falls within the effective separation range, preventing unwanted interactions and compromising purity.
  • Use stabilizing buffers that support protein integrity: All proteins have unique and individualized stability requirements, so researchers must carefully choose buffers that maintain the protein’s native structure and prevent its denaturation or aggregation during the separation process.
  • Balance flow rates for optimal resolution: Controlling the flow rate is essential, as faster flow rates can reduce separation efficiency. In comparison, slower rates can lead to excessive diffusion and broader peaks.
  • Avoid column overloading to maintain separation quality: Overloading the column with too much protein sample can cause poor separation and overlapping peaks, diminishing the overall resolution and purity of the final product.

G-Biosciences offers the following products to enhance SEC workflows. As protein research evolves, robust purification methods are more important than ever

Figure 1: Size exclusion column:

Protein Purification Handbook

References:

  1. Passos, C. et al (2025) BioRxiv, page 29. https://doi.org/10.1101/2025.03.11.642215
  2. Huang, X. et al (2023) VIROL J. https://doi.org/10.1186/s12985-023-01964-w
  3. Choo, KK. et al. (2020) Original Rep. 24:30
  4. Yin, Z. et al (2017) Nucleic Acids Research. https://doi.org/10.1093/nar/gkx795
  5. Dambacher, C. M. et al (2015) J. Struct. Biol. DOI:10.1016/j.jsb.2015.09.010