Hierarchy of Biological Complexity Macromolecular machines Protein and nucleic acid structure Sequences

"It is very easy to answer many of these fundamental biological questions; you just look at the thing!... Make the microscope one hundred times more powerful, and many problems of biology would be made very much easier. I exaggerate, of course, but the biologists would surely be very thankful to you — and they would prefer that to the criticism that they should use more mathematics.“ Richard P. Feynman. From There's Plenty of Room at the Bottom, a lecture given to the American Physical Society in 1959.

Low resolution data on entire complex (EM) + High resolution data on individual components (x-ray / NMR) High resolution model of complex Verification of model by difference mapping / labeling Structure: what does it look like?

Mt-K.ADP Mt-K.ADP.Pi Mt-K.ATP Mt-K Mt-K.ADP ADP Pi ATP MtK.ADP

Mechanism: how does it work? Hypothesis driven Attachment of reporters to visualize conformational changes Trapping in defined parts of its cycle

7.6 A 88,000x Raft 11.5 A x

Typical doses accumulated during automated acquisition e/A e/A e/A 2 550x 1700x100000x Leginon I setup for TMV data acquisition