Novel Developments in Cryo-em of Biological Molecules : Resolution in Time and State Space

Cryo-EM, as it is currently practiced in many laboratories, is limited to the visualization of molecules that are in thermal equilibrium at the time before freezing. A further limitation is that the existing software does not fully exploit the information that is contained in the images of large ensembles of molecules in thermal equilibrium. This book is a collection of recent articles by the author, reprinted with introductions, and they mainly describe two novel methods in cryo-EM, one computational and the other experimental that requires the use of a microfluidic device. Both methods have the capacity to shed light on the dynamic behavior of biomolecules. Combined, they greatly expand the range of applications of cryo-EM.

The book describes a successful approach in which, based on cryo-EM data, all states visited by the molecule in thermal equilibrium are mapped by manifold embedding―a method of geometric machine learning―and the energy landscape of the molecule is derived. It also discusses methods and biological results of time-resolved cryo-EM, following a reaction in a non-equilibrium system over a short period of time and resulting in the capture of short-lived states that have been inaccessible by standard methods of cryo-EM.

Joachim Frank is a professor of biochemistry and molecular biophysics and of biological sciences at Columbia University, USA. Dr. Frank’s lab has developed techniques of single-particle reconstruction of biological macromolecules, specializing in mathematical and computational approaches. He has applied these techniques of visualization to explore the structure and dynamics of the ribosomes during the process of protein synthesis and to elucidate the structure and function of several ion channels. He is a member of the National Academy of Sciences and of the American Academy of Microbiology. He is also a fellow of the American Academy of Arts and Sciences and of the American Association for the Advancement of Science. In 2014, he was honored with the Franklin Medal for Life Sciences. In 2017, he shared the Wiley Prize in Biomedical Sciences with Richard Henderson and Marin van Heel. He was awarded the 2017 Nobel Prize in Chemistry together with Jacques Dubochet and Richard Henderson for "developing cryo-electron microscopy for the high-resolution structure determination of biomolecules in solution."