Data Assimilation to Integrate High-Speed Atomic Force Microscopy with Biomolecular Simulations: Characterization of Drug Target Functions

In drug development pipelines, the early phase contains characterization of the target biomolecules/genes and screening assay of inhibitors on the target function. For this purpose, direct observation of single biomolecules at work should be very powerful but is also extremely challenging. Among many single-molecule techniques, high-speed atomic force microscopy (HS-AFM) is unique in that it observes structure and dynamics of single biomolecules in real time under near-physiological conditions. While largely improved, however, the current AFM has limited resolution both in time and space. Recently, we developed an assimilation method of HS-AFM data using molecular dynamics (MD) simulations, which provide information with a very high spatiotemporal resolution. This chapter begins with a brief introduction to HS-AFM. In the following three sections, we describe various computational analyses recently developed to obtain molecular-level structural and dynamical information of biomolecules from HS-AFM data. Next, recent advances in experimental equipment are introduced. Finally, the latest research tackling cell biology problems using HS-AFM are presented.