Abstract
Roderick MacKinnon:
It has been more than 70 years since the first structures of proteins and DNA were determined, and by now scientists have described the structures of a vast number of biological macromolecules, including very complex, multi-protein machines. At least one conformation of ~ 15% of proteins encoded in the human genome have been determined experimentally, and the protein structure database on all organisms is large enough to have trained a neural network programme – AlphaFold – to extrapolate most of the structures. It is thus natural to ask, is structural biology nearly complete? To answer this question, we must recognize that the size of biological macromolecules is on the order of 1-100 nm3, whereas the size of a small cell is about a billion times larger. Therefore, much of life’s chemistry occurs through non-covalent interactions, which we know very little about. New methods have been developed recently that promise to advance our understanding of the rules of non-covalent assembly in biology. To inspire a discussion on this general topic, I will present evidence that simple rules may underlie patterns of membrane proteins essential to cell signaling.
Sir John E. Walker:
Our aim as structural, molecular, and cell biologists, biochemists, and biophysicists, is to understand life at the molecular level. Recent spectacular advances in our ability to predict protein structures with AlphaFold have led to the mistaken view that structural biology is approaching being "finished" and "dead". Nothing could be further from the truth. In my own restricted field of mitochondrial biology, thanks to structural biology, and especially electron cryo-microscopy, we can now describe many of the fundamental processes that lie behind the formation of adenosine triphosphate (ATP), including oxidative phosphorylation, glycolysis, the TCA cycle, fatty acid oxidation, the associated transport processes, import of nuclear encoded proteins, mitochondrial DNA replication, transcription, and protein synthesis in ever increasing exquisite detail. However, to take the ATP synthase as an example, can Alphafold predict the structure and functioning of this complex machine, and the pathways of its assembly from first principles? Proteins are inherently dynamic and change their properties depending on an infinite number of dynamic states under the influence of thermal energy. Proteins are also engaged in dynamic interactions, which changes the way they may function. Static views, whether solved by experimental or computational methods, do not capture these fundamental properties. Other challenges relate to the formation, properties, and roles of biomolecular condensates of proteins that form, for example during the imperfect import of proteins into mitochondria or the condensates of proteins plus nucleic acids that constitute the mitochondrial nucleoid. Thus, there are plenty of outstanding challenges for structural biology, which can be addressed by structural and biophysical techniques as well as Alphafold.
