Dynamic structural biology: Bringing the structures of nucleic acids to life
One of the goals of biomedical science is to achieve a predictive understanding of living cells, tissues, and ultimately whole organisms based on the activities of their constituent biomolecules. Such an understanding could have far reaching implications for synthetic biology and drug discovery. Structural biologists have sought to understand how biological macromolecules carry out their cellular functions by solving their three-dimensional structure at atomic resolution. Yet, after five decades of the structure-function paradigm, including the recent ‘resolution revolution’ in cryo electron microscopy, we still lack a deep predictive understanding of how even the simplest proteins and nucleic acids work. Key biochemical properties of interest such as catalytic efficiency, specificity, fidelity, and stability cannot be deduced from static structures or even collections of static structures in different states. Rather, it is now abundantly clear that the biomolecules function through multi-step biochemical reactions during which they undergo critically important changes in their conformation. In this lecture, I will describe how the intrinsic thermodynamic propensities and kinetic rates with which biomolecules change their 3D structures (i.e. structural dynamics) can determine the kinetics of microscopic reaction steps and ultimately their biochemical properties and cellular activities. I will describe how solution state NMR spectroscopy is helping to reveal many layers of structural dynamics in DNA and RNA over picosecond to millisecond timescales that drive processes essential to life and disease. From these and other studies, a new paradigm for dynamic structural biology is beginning to emerge.