UCSF

The twin subjects of this dissertation may seem far flung, but they are unified by a commonpurpose. I like stories that start with molecules and end with things everyone has directly experienced. That is, I’m interested in bridging the gaps between macro-scale physiology and molecular sciences, that we might give an account of our immediate experiences on a solid foundation. Each project involved completely different collaborators and methods, but both were integral to my time at UCSF and directed by the same underlying curiosity. One crucial question at this meso-scale interface is how proteins deform and ultimately determine the fate of membranes. An exemplary membrane-deforming protein is the M2 proton channel, produced by influenza to help the virus escape the host cell. I combined molecular dynamics simulations with diverse experimental measurements to better understand the structural principles that allow M2 to bind curved membranes and facilitate the release of new virions. In unbiased simulations, I find that M2 spontaneously loses its initial four-fold symmetry to become at most two-fold symmetric. This dynamical property seemed potentially connected to its ability to accommodate negative Gaussian curvature (a saddle-shaped membrane geometry). Additional simulations agree with continuum membrane calculations that two-fold symmetry is better adapted to saddleshaped membranes, suggesting that symmetry degeneration is a key part of M2’s function in viral egress. Therapeutics may one day be able to alter this property and inhibit influenza egress. These findings may be generalizable to other viroporins like the SARS-CoV2 E protein. Another key meso-scale question is how neuroactive drugs give rise to behavioral changes in animals. I helped develop a platform for investigating drug-induced behavioral phenotypes in larval zebrafish at scale in order to begin quantitative mapping between chemical matter (drugs) and simple but fundamental behaviors like sedation and habituation. We find that known drugs habituation modifiers (like MK-801) are effective in the larval zebrafish model, and identified several new lead compounds from libraries with similar effects. Such drugs may hold promise as treatments for addiction and neurodegeneration.