Integrating simulation and experiment for advanced characterization of multi-domain protein dynamics

Protein flexibility and dynamics are central to molecular interactions, and, therefore, to biological function. Monoclonal antibody (mAb) therapeutics—a rapidly expanding class of biopharmaceuticals—are flexible proteins a few nanometers in size with multiple domains. Their dynamic processes have the potential to influence both therapeutic efficacy and stability during storage. Accurately capturing internal domain motions of mAbs at nanosecond and nanometer scale remains a great challenge. Here, we use molecular dynamics (MD) simulations of the NIST Monoclonal Antibody Reference Material 8671 (NISTmAb), a well-characterized model system, to provide a detailed and quantitative view of the relevant macromolecular dynamics. Comparison with experimental neutron spin echo data enables an integrative approach to characterizing multi-domain protein motions. Our results create a framework for assessing nano length- and time-scale dynamics which can ultimately lead to predictive and rational biotherapeutic design.