A Quantitative Description for Optical Mass Measurement of Single Biomolecules

Label-free detection of single biomolecules in solution has been achieved using a variety experimental approaches over the past decade. Yet, our understanding magnitude optical contrast and its relationship with underlying atomic structure as well achievable measurement sensitivity precision remain poorly defined. Here, we use Fourier optics approach combined an structure-based molecular polarizability model to simulate mass photometry experiments from first principles. We find excellent agreement between several key experimentally determined parameters such contrast-to-mass conversion, accuracy, shape orientation dependence. This allows us determine mostly independent chosen, resulting general framework for light-based single-molecule quantification.