An international research team led by Dr. Adolfo Poma (Institute of Fundamental Technological Research, Polish Academy of Sciences – IPPT PAN, Warsaw), in collaboration with Dr. Luis Fernando Cofas-Vargas (Universidad Autónoma Metropolitana-Iztapalapa, Mexico) and Prof. Siewert J. Marrink (University of Groningen, The Netherlands), has identified a previously overlooked factor that influences how antibodies neutralize SARS-CoV-2: their mechanical stability under force.

SARS-CoV-2_scanning_electron_microscope_image (1)

Source: National Institute of Allergy and Infectious Diseases (NIAID)

Novel Coronavirus SARS-CoV-2 ; This scanning electron microscope image shows SARS-CoV-2 (round gold objects) emerging from the surface of cells cultured in the lab.

Antibodies are key components of the immune system that bind to viral particles and block infection. Traditionally, their effectiveness has been evaluated based on binding affinity alone—how strongly they attach to viral proteins. However, in the human body, antibodies function in a mechanically dynamic environment shaped by blood flow, respiratory motion, and cellular forces.

In a study published in Physical Chemistry Chemical Physics, the researchers used advanced computer simulations to investigate how antibody–virus complexes respond to mechanical forces across multiple SARS-CoV-2 variants, including the original 2019 strain and Omicron subvariants BA.4 and JN.1.

Two binding arms

The team compared conventional Y-shaped antibodies with nanobodies—smaller, single-domain proteins originally discovered in camelids such as llamas. While nanobodies are increasingly studied as therapeutic candidates due to their stability and compact structure, antibodies can bind more strongly because they have two binding arms.

The simulations revealed that conventional antibodies distribute mechanical load unevenly: the heavy chain bears most of the force, while the light chain provides structural reinforcement. Together, they form a cooperative system capable of resisting forces of approximately 500 piconewtons. Importantly, the intact antibody structure is mechanically stronger than its individual components, as removing either chain significantly reduces stability.

Low-Res_full-cover-Poma

This visualization shows the SARS-CoV-2 spike protein bound to an antibody being mechanically probed via virtual AFM-SMFS in GōMartini 3 simulations, revealing force-driven dissociation pathways and molecular mechanical responses.CreditImage reproduced by permission of Adolfo B. Poma and Gustavo E. Olivos-Ramírez from Physical Chemistry Chemical Physics, 2026, 28, 8997-8997. https://doi.org/10.1039/D6CP90075E

The study also shows that viral mutations influence not only binding affinity but also mechanical resistance. The BA.4 variant tends to increase the mechanical stability of several antibody–virus complexes, whereas the JN.1 variant is associated with reduced stability, suggesting that SARS-CoV-2 evolution may have involved adaptation to mechanical as well as biochemical pressures.

Partial unfolding

In several cases, mechanical forces lead to partial unfolding of specific regions of the viral spike protein during antibody detachment. These mechanically vulnerable sites may represent promising targets for future therapeutic design.

“Our results demonstrate that antibody effectiveness cannot be fully understood through binding affinity alone,” said Dr. Adolfo Poma. “Mechanical stability plays a crucial role under physiological conditions and should be considered in future therapeutic design.”

The findings introduce a new design principle for antibody engineering that integrates both biochemical and mechanical perspectives. This approach could improve therapeutic strategies against SARS-CoV-2 and other diseases where antibody-based treatments are used, including cancer.

The study was featured on the cover of the journal.

Topics