Unveiling the Structural and Mechanical Diversity of SARS-CoV-2 Variants Using Atomic Force Microscopy

Understanding the structure and virion-host interaction of SARS-CoV-2 is crucial for elucidating the fundamental mechanisms of its assembly, stability, and transmission. These insights not only improve antiviral strategies but also contribute to a broader understanding of the nanoscale biological systems. Most studies of coronavirus focus primarily on viral genetics and on the structure and receptor affinity of the spike protein but overlook the broader mechanical and structural properties of the virion as a whole. Several studies have already suggested structural variability among coronavirus virions, and our work aims to provide more evidence of this matter. Here, we studied chemically fixed SARS-CoV-2 variants, focusing on wild-type, alpha, and delta variants. We used atomic force microscopy to acquire high-resolution topographic information. To estimate physically plausible virion envelope shapes, we utilized the Helfrich vesicle model as part of the analysis pipeline. We estimated viral geometry and adhesional compliance through reduced volume and its relationship with other geometrical parameters. We revealed consistent differences in apparent virion geometry across the three variants with alpha and delta displaying smaller fitted envelopes and lower reduced-volume estimates than wild-type under identical capture, fixation, and imaging conditions. Geometry-derived contact metrics also differed systematically among variants, consistent with differences in apparent deformation and compliance in this assay. Together, these descriptors establish a comparative framework for assessing the variant-dependent virion geometry and apparent deformation behavior.