Abstract:
Life depends on molecular machines that move—polymerases copying DNA, helicases unwinding it, ribosomes translating RNA. Yet most of our knowledge comes from static structures, like photos of dancers frozen mid-step. What we really need is the choreography: how molecules shift from one state to another, and how these motions drive function.
Cryo-electron microscopy (cryo-EM), awarded the 2017 Nobel Prize in Chemistry, is now being used not only to determine static structures but also to capture motion. By analyzing the natural variability in cryo-EM data, we can extract trajectories of molecular movement. Using the SV40 Large T-antigen helicase as an example, I will show how particle variability analysis (3DVA) reveals DNA being translocated step by step during ATP hydrolysis. These results challenge the classical “power stroke” model and suggest that enzymes harness thermal fluctuations, with ATP hydrolysis acting as a switch to bias motion forward.

This talk highlights how studying structural dynamics allows us to re-define fundamental mechanisms at the atomic-scale level.

Bio:
Alfredo De Biasio is an Assistant Professor in the BESE Division at KAUST. His research focuses on the structural biology of DNA replication and repair, using cryo-electron microscopy (cryo-EM) to visualize how large protein machines work at near-atomic resolution. He obtained his PhD from Scuola Normale Superiore in Italy and carried out postdoctoral work in Spain before establishing his independent group in the UK. He moved to KAUST in 2021. Alfredo’s lab has contributed key insights into the mechanisms of DNA polymerases and helicases, including a recent study published in Nature that revealed how replicative helicases unwind DNA in motion.